STRADA

Gene Summary

Gene:STRADA; STE20-related kinase adaptor alpha
Aliases: LYK5, PMSE, Stlk, STRAD, NY-BR-96
Location:17q23.3
Summary:The protein encoded by this gene contains a STE20-like kinase domain, but lacks several residues that are critical for catalytic activity, so it is termed a 'pseudokinase'. The protein forms a heterotrimeric complex with serine/threonine kinase 11 (STK11, also known as LKB1) and the scaffolding protein calcium binding protein 39 (CAB39, also known as MO25). The protein activates STK11 leading to the phosphorylation of both proteins and excluding STK11 from the nucleus. The protein is necessary for STK11-induced G1 cell cycle arrest. A mutation in this gene has been shown to result in polyhydramnios, megalencephaly, and symptomatic epilepsy (PMSE) syndrome. Multiple transcript variants encoding different isoforms have been found for this gene. Additional transcript variants have been described but their full-length nature is not known. [provided by RefSeq, Sep 2009]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:STE20-related kinase adapter protein alpha
Source:NCBIAccessed: 11 March, 2017

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: STRADA (cancer-related)

Conconi D, Sala E, Bovo G, et al.
Using Copy Number Alterations to Identify New Therapeutic Targets for Bladder Carcinoma.
Int J Mol Sci. 2016; 17(3):271 [PubMed] Free Access to Full Article Related Publications
Bladder cancer represents the ninth most widespread malignancy throughout the world. It is characterized by the presence of two different clinical and prognostic subtypes: non-muscle-invasive bladder cancers (NMIBCs) and muscle-invasive bladder cancers (MIBCs). MIBCs have a poor outcome with a common progression to metastasis. Despite improvements in knowledge, treatment has not advanced significantly in recent years, with the absence of new therapeutic targets. Because of the limitations of current therapeutic options, the greater challenge will be to identify biomarkers for clinical application. For this reason, we compared our array comparative genomic hybridization (array-CGH) results with those reported in literature for invasive bladder tumors and, in particular, we focused on the evaluation of copy number alterations (CNAs) present in biopsies and retained in the corresponding cancer stem cell (CSC) subpopulations that should be the main target of therapy. According to our data, CCNE1, MYC, MDM2 and PPARG genes could be interesting therapeutic targets for bladder CSC subpopulations. Surprisingly, HER2 copy number gains are not retained in bladder CSCs, making the gene-targeted therapy less interesting than the others. These results provide precious advice for further study on bladder therapy; however, the clinical importance of these results should be explored.

Canal F, Anthony E, Lescure A, et al.
A kinome siRNA screen identifies HGS as a potential target for liver cancers with oncogenic mutations in CTNNB1.
BMC Cancer. 2015; 15:1020 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Aberrant activation of the Wnt/β-catenin pathway is a major and frequent event in liver cancer, but inhibition of oncogenic β-catenin signaling has proven challenging. The identification of genes that are synthetically lethal in β-catenin-activated cancer cells would provide new targets for therapeutic drug design.
METHODS: We transfected the parental HuH6 hepatoblastoma cell line with a doxycycline-inducible shRNA against CTNNB1 (gene coding for β-catenin) to obtain an isogenic cell line pair with or without aberrant β-catenin signaling. Using this hepatoblastoma isogenic cell line pair, we performed a human kinome-wide siRNA screen to identify synthetic lethal interactions with oncogenic CTNNB1. The phenotypic readouts of the screen were cell proliferation, cell cycle arrest and apoptosis, which were assessed by image-based analysis. In addition, apoptosis was assessed by flow cytometric experiments and immunoblotting. The potential synthetic lethal relationship between candidates genes identified in the screen and oncogenic CTNNB1 was also investigated in a different cellular context, a colorectal HCT116 isogenic cell line pair.
RESULTS: We first determined the experimental conditions that led to the efficient expression of shRNA against CTNNB1 and maximal reduction of β-catenin signaling activity in response to doxycycline treatment. Following high throughput screening in which 687 genes coding for kinases and proteins related to kinases (such as pseudokinases and phosphatases) were targeted, we identified 52 genes required for HuH6 survival. The silencing of five of these genes selectively impaired the viability of HuH6 cells with high β-catenin signaling: HGS, STRADA, FES, BRAF and PKMYT1. Among these candidates, HGS depletion had the strongest inhibitory effect on cell growth and led to apoptosis specifically in HuH6 with high β-catenin activity, while HuH6 with low β-catenin activity were spared. In addition, HGS was identified as a potential synthetic lethal partner of oncogenic CTNNB1 in the HCT116 colorectal isogenic cell line pair.
CONCLUSIONS: These results demonstrate the existence of crosstalk between β-catenin signaling and HGS. Importantly, HGS depletion specifically affected cells with uncontrolled β-catenin signaling activity in two different types of cancer (Hepatoblastoma HuH6 and colorectal HCT116), and thus may represent a new potential target for novel therapeutic strategies in liver and colorectal cancer.

Bonin S, Donada M, Bussolati G, et al.
A synonymous EGFR polymorphism predicting responsiveness to anti-EGFR therapy in metastatic colorectal cancer patients.
Tumour Biol. 2016; 37(6):7295-303 [PubMed] Related Publications
Genetic factors are known to affect the efficiency of therapy with monoclonal antibodies (mAbs) targeting the epidermal growth factor receptor (EGFR) in patients with metastatic colorectal cancer (mCRC). At present, the only accepted molecular marker predictive of the response to anti-EGFR mAbs is the somatic mutation of KRAS and NRAS as a marker of resistance to anti-EGFR. However, only a fraction of KRAS wild-type patients benefit from that treatment. In this study, we show that the EGFR gene polymorphism rs1050171 defines, independently of RAS mutational status, a sub-population of 11 % of patients with a better clinical outcome after anti-EGFR treatment. Median PFS for patients with the GG genotype was 10.17 months compared to 5.37 of those with AG + AA genotypes. Taken together, our findings could be used to better define CRC populations responding to anti-EGFR therapy. Further studies in larger independent cohorts are necessary to validate the present observation that a synonymous polymorphism in EGFR gene impacts on clinical responsiveness.

Cavalloni G, Peraldo-Neia C, Varamo C, et al.
Establishment and characterization of a human intrahepatic cholangiocarcinoma cell line derived from an Italian patient.
Tumour Biol. 2016; 37(3):4041-52 [PubMed] Free Access to Full Article Related Publications
Biliary tract carcinoma is a rare malignancy with multiple causes, which underlie the different genetic and molecular profiles. Cancer cell lines are affordable models, reflecting the characteristics of the tumor of origin. They represent useful tools to identify molecular targets for treatment. Here, we established and characterized from biological, molecular, and genetic point of view, an Italian intrahepatic cholangiocarcinoma cell line (ICC), the MT-CHC01. MT-CHC01 cells were isolated from a tumor-derived xenograft. Immunophenotypical characterization was evaluated both at early and after stabilization passages. In vitro biological, genetic, and molecular features were also investigated. In vivo tumorigenicity was assessed in NOD/SCID mice. MT-CHC01cells retain epithelial cell markers, EPCAM, CK7, and CK19, and some stemness and pluripotency markers, i.e., SOX2, Nanog, CD49f/integrin-α6, CD24, PDX1, FOXA2, and CD133. They grow as a monolayer, with a population double time of about 40 h; they show a low migration and invasion potential. In low attachment conditions, they are able to form spheres and to growth in anchorage-independent manner. After subcutaneous injection, they retain in vivo tumorigenicity; the expression of biliary markers as CA19-9 and CEA were maintained from primary tumor. The karyotype is highly complex, with a hypotriploid to hypertriploid modal number (3n+/-) (52 to 77 chromosomes); low level of HER2 gene amplification, TP53 deletion, gain of AURKA were identified; K-RAS G12D mutation were maintained from primary tumor to MT-CHC01 cells. We established the first ICC cell line derived from an Italian patient. It will help to study either the biology of this tumor or to test drugs both in vitro and in vivo.

Errichiello E, Balsamo A, Cerni M, Venesio T
Mitochondrial variants in MT-CO2 and D-loop instability are involved in MUTYH-associated polyposis.
J Mol Med (Berl). 2015; 93(11):1271-81 [PubMed] Related Publications
UNLABELLED: Mitochondrial DNA alterations have been widely reported in different human tumours, including colorectal carcinoma, but their mutational spectrum and pathogenic role in specific subsets of patients with polyposis syndromes have been poorly investigated. We compared the breadth of somatic variants across the mitochondrial genome of MUTYH-associated polyposis (MAP) patients with homogeneous groups of classical/attenuated familial adenomatous polyposis (FAP/AFAP) and sporadic cases. Overall, we screened 121 adenomas and seven adenocarcinomas and their corresponding germinal controls, for mitochondrial genes with a crucial role in oxidative phosphorylation and translation (MT-CO1, MT-CO2, MT-CO3, MT-TD, MT-TS1, MT-ATP6) as well as a hypervariable sequence (HV-II) within the control region displacement loop (D-loop), a marker of hypermutability and clonal expansion. The sequencing analysis revealed the presence of 17 variants, mostly causing non-synonymous changes in conserved amino acid residues, typically distributed in the MT-CO2 gene of MAP patients (P < 0.0001), who frequently carried the hot spot m.7763G>A variant. Accordingly, D-loop instability was also significantly associated with variants grouped inside the MT-CO2 gene (P = 0.0061). This is the first report showing a locus-specific distribution of mitochondrial DNA alterations in a subtype of colorectal tumourigenesis. In addition, our findings suggest that MT-CO2 variants, representing early molecular events in MAP tumorigenesis, might be a potential prognostic biomarker for the cancer-risk assessment of patients affected by this syndrome.
KEY MESSAGES: We compared the frequencies of mtDNA variants in MAP vs. FAP/AFAP/sporadic patients. We found a gene-specific (MT-CO2) distribution of mtDNA variants in MAP cases. Most mtDNA variants caused non-synonymous changes in conserved amino acid residues. D-loop instability was significantly associated with variants grouped inside MT-CO2. MT-CO2 variants might be a potential prognostic biomarker in MAP patients.

Dando I, Cordani M, Dalla Pozza E, et al.
Antioxidant Mechanisms and ROS-Related MicroRNAs in Cancer Stem Cells.
Oxid Med Cell Longev. 2015; 2015:425708 [PubMed] Free Access to Full Article Related Publications
Increasing evidence indicates that most of the tumors are sustained by a distinct population of cancer stem cells (CSCs), which are responsible for growth, metastasis, invasion, and recurrence. CSCs are typically characterized by self-renewal, the key biological process allowing continuous tumor proliferation, as well as by differentiation potential, which leads to the formation of the bulk of the tumor mass. CSCs have several advantages over the differentiated cancer cell populations, including the resistance to radio- and chemotherapy, and their gene-expression programs have been shown to correlate with poor clinical outcome, further supporting the relevance of stemness properties in cancer. The observation that CSCs possess enhanced mechanisms of protection from reactive oxygen species (ROS) induced stress and a different metabolism from the differentiated part of the tumor has paved the way to develop drugs targeting CSC specific signaling. In this review, we describe the role of ROS and of ROS-related microRNAs in the establishment and maintenance of self-renewal and differentiation capacities of CSCs.

Tomaselli S, Galeano F, Alon S, et al.
Modulation of microRNA editing, expression and processing by ADAR2 deaminase in glioblastoma.
Genome Biol. 2015; 16:5 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: ADAR enzymes convert adenosines to inosines within double-stranded RNAs, including microRNA (miRNA) precursors, with important consequences on miRNA retargeting and expression. ADAR2 activity is impaired in glioblastoma and its rescue has anti-tumoral effects. However, how ADAR2 activity may impact the miRNome and the progression of glioblastoma is not known.
RESULTS: By integrating deep-sequencing and array approaches with bioinformatics analyses and molecular studies, we show that ADAR2 is essential to edit a small number of mature miRNAs and to significantly modulate the expression of about 90 miRNAs in glioblastoma cells. Specifically, the rescue of ADAR2 activity in cancer cells recovers the edited miRNA population lost in glioblastoma cell lines and tissues, and rebalances expression of onco-miRNAs and tumor suppressor miRNAs to the levels observed in normal human brain. We report that the major effect of ADAR2 is to reduce the expression of a large number of miRNAs, most of which act as onco-miRNAs. ADAR2 can edit miR-222/221 and miR-21 precursors and decrease the expression of the corresponding mature onco-miRNAs in vivo and in vitro, with important effects on cell proliferation and migration.
CONCLUSIONS: Our findings disclose an additional layer of complexity in miRNome regulation and provide information to better understand the impact of ADAR2 editing enzyme in glioblastoma. We propose that ADAR2 is a key factor for maintaining edited-miRNA population and balancing the expression of several essential miRNAs involved in cancer.

Peraldo-Neia C, Cavalloni G, Soster M, et al.
Anti-cancer effect and gene modulation of ET-743 in human biliary tract carcinoma preclinical models.
BMC Cancer. 2014; 14:918 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Standard chemotherapy in unresectable biliary tract carcinoma (BTC) patients is based on gemcitabine combined with platinum derivatives. However, primary or acquired resistance is inevitable and no second-line chemotherapy is demonstrated to be effective. Thus, there is an urgent need to identify new alternative (chemo)therapy approaches.
METHODS: We evaluated the mechanism of action of ET-743 in preclinical models of BTC. Six BTC cell lines (TFK-1, EGI-1, TGBC1, WITT, KMCH, HuH28), two primary cell cultures derived from BTC patients, the EGI-1 and a new established BTC patient-derived xenografts, were used as preclinical models to investigate the anti-tumor activity of ET-743 in vitro and in vivo. Gene expression profiling was also analyzed upon ET-743 treatment in in vivo models.
RESULTS: We found that ET-743 inhibited cell growth of BTC cell lines and primary cultures (IC50 ranging from 0.37 to 3.08 nM) preferentially inducing apoptosis and activation of the complex DNA damage-repair proteins (p-ATM, p-p53 and p-Histone H2A.x) in vitro. In EGI-1 and patient-derived xenografts, ET-743 induced tumor growth delay and reduction of vasculogenesis. In vivo ET-743 induced a deregulation of genes involved in cell adhesion, stress-related response, and in pathways involved in cholangiocarcinogenesis, such as the IL-6, Sonic Hedgehog and Wnt signaling pathways.
CONCLUSIONS: These results suggest that ET-743 could represent an alternative chemotherapy for BTC treatment and encourage the development of clinical trials in BTC patients resistant to standard chemotherapy.

Danielli R, Patuzzo R, Ruffini PA, et al.
Armed antibodies for cancer treatment: a promising tool in a changing era.
Cancer Immunol Immunother. 2015; 64(1):113-21 [PubMed] Related Publications
Advances in the understanding of tumor immunology and molecular biology of melanoma cells have favored a larger application of immunotherapy and targeted therapies in the clinic. Several selective mutant gene inhibitors and immunomodulating antibodies have been reported to improve overall survival or progression-free survival in metastatic melanoma patients. However, despite impressive initial responses, patients treated with selective inhibitors relapse quickly, and toxicities associated to the use of immunomodulating antibodies are not easily manageable. In this sense, the concept of using antibodies as delivery vehicles for the preferential in vivo localization of the drug at the site of disease with reduction of side effects has raised particular interest. Antibody-cytokine fusion proteins (termed immunocytokines) represent a new simple and effective way to deliver the immunomodulatory payload at the tumor site, with the aim of inducing both local and systemic antitumoral immune responses and limiting systemic toxicities. Several clinical trials have been conducted and are actually ongoing with different immunocytokines, in several tumor histotypes. In metastatic melanoma patients, different drug delivery modalities such as systemic, loco-regional and intratumoral are under investigation. In this review, the rationale for the use of L19-IL2 and L19-TNF, two clinical stage immunocytokines produced by the Philogen group, as well as opportunities for their future development will be discussed.

Rolland Y, Marighetti P, Malinverno C, et al.
The CDC42-interacting protein 4 controls epithelial cell cohesion and tumor dissemination.
Dev Cell. 2014; 30(5):553-68 [PubMed] Related Publications
The role of endocytic proteins and the molecular mechanisms underlying epithelial cell cohesion and tumor dissemination are not well understood. Here, we report that the endocytic F-BAR-containing CDC42-interacting protein 4 (CIP4) is required for ERBB2- and TGF-β1-induced cell scattering, breast cancer (BC) cell motility and invasion into 3D matrices, and conversion from ductal breast carcinoma in situ to invasive carcinoma in mouse xenograft models. CIP4 promotes the formation of an E-cadherin-CIP4-SRC complex that controls SRC activation, E-cadherin endocytosis, and localized phosphorylation of the myosin light chain kinase, thereby impinging on the actomyosin contractility required to generate tangential forces to break cell-cell junctions. CIP4 is upregulated in ERBB2-positive human BC, correlates with increased distant metastasis, and is an independent predictor of poor disease outcome in subsets of BC patients. Thus, it critically controls cell-cell cohesion and is required for the acquisition of an invasive phenotype in breast tumors.

Van Emburgh BO, Sartore-Bianchi A, Di Nicolantonio F, et al.
Acquired resistance to EGFR-targeted therapies in colorectal cancer.
Mol Oncol. 2014; 8(6):1084-94 [PubMed] Related Publications
Cetuximab and panitumumab are anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibodies used as therapies for metastatic colorectal cancer patients. Intrinsic mechanisms of resistance, such as RAS mutations, can prevent patients from having a response with clinical benefit. The clinical efficacy of EGFR targeted antibodies is limited by the development of acquired (secondary) resistance, which typically occurs within 3-12 months from the start of therapy. Preclinical models and analyses of clinical samples have uncovered some of the alterations that confer a selective advantage to tumor cells when under the pressure of anti-EGFR therapy. Molecular profiling of clinical specimens confirmed that genetic alterations of genes in the EGFR-RAS-RAF-MEK signaling pathway and of receptor tyrosine kinases are mechanisms of acquired resistance to anti-EGFR antibodies. The escape from anti-EGFR blockade appears to converge on the (re)activation of MEK-ERK or AKT as revealed in preclinical studies. Circulating tumor DNA and patient derived xenografts have proven useful tools to monitor patients for resistance to anti-EGFR therapy and test combination therapies to overcome or reverse resistance.

Vigna E, Pacchiana G, Chiriaco C, et al.
Targeted therapy by gene transfer of a monovalent antibody fragment against the Met oncogenic receptor.
J Mol Med (Berl). 2014; 92(1):65-76 [PubMed] Related Publications
UNLABELLED: Due to the key role played in critical sub-populations, Met is considered a relevant therapeutic target for glioblastoma multiforme and lung cancers. The anti-Met DN30 antibody, engineered to a monovalent Fab (Mv-DN30), proved to be a potent antagonist, inducing physical removal of Met receptor from the cell surface. In this study, we designed a gene therapy approach, challenging Mv-DN30 in preclinical models of Met-driven human glioblastoma and lung carcinoma. Mv-DN30 was delivered by a Tet-inducible-bidirectional lentiviral vector. Gene therapy solved the limitations dictated by the short half-life of the low molecular weight form of the antibody. In vitro, upon doxycycline induction, the transgene: (1) drove synthesis and secretion of the correctly assembled Mv-DN30; (2) triggered the displacement of Met receptor from the surface of target cancer cells; (3) suppressed the Met-mediated invasive growth phenotype. Induction of transgene expression in cancer cells-transplanted either subcutaneously or orthotopically in nude mice-resulted in inhibition of tumor growth. Direct Mv-DN30 gene transfer in nude mice, intra-tumor or systemic, was followed by a therapeutic response. These results provide proof of concept for a gene transfer immunotherapy strategy by a Fab fragment and encourage clinical studies targeting Met-driven cancers with Mv-DN30.
KEY MESSAGE: Gene transfer allows the continuous in vivo production of therapeutic Fab fragments. Mv-DN30 is an excellent tool for the treatment of Met-driven cancers. Mv-DN30 gene therapy represents an innovative route for Met targeting.

Crowley E, Di Nicolantonio F, Loupakis F, Bardelli A
Liquid biopsy: monitoring cancer-genetics in the blood.
Nat Rev Clin Oncol. 2013; 10(8):472-84 [PubMed] Related Publications
Cancer is associated with mutated genes, and analysis of tumour-linked genetic alterations is increasingly used for diagnostic, prognostic and treatment purposes. The genetic profile of solid tumours is currently obtained from surgical or biopsy specimens; however, the latter procedure cannot always be performed routinely owing to its invasive nature. Information acquired from a single biopsy provides a spatially and temporally limited snap-shot of a tumour and might fail to reflect its heterogeneity. Tumour cells release circulating free DNA (cfDNA) into the blood, but the majority of circulating DNA is often not of cancerous origin, and detection of cancer-associated alleles in the blood has long been impossible to achieve. Technological advances have overcome these restrictions, making it possible to identify both genetic and epigenetic aberrations. A liquid biopsy, or blood sample, can provide the genetic landscape of all cancerous lesions (primary and metastases) as well as offering the opportunity to systematically track genomic evolution. This Review will explore how tumour-associated mutations detectable in the blood can be used in the clinic after diagnosis, including the assessment of prognosis, early detection of disease recurrence, and as surrogates for traditional biopsies with the purpose of predicting response to treatments and the development of acquired resistance.

Donada M, Bonin S, Barbazza R, et al.
Management of stage II colon cancer - the use of molecular biomarkers for adjuvant therapy decision.
BMC Gastroenterol. 2013; 13:36 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: There is uncertainty on the benefit of adjuvant chemotherapy in patients with stage II colorectal cancers. The aim of this study is to investigate the combined role of clinical, pathological and molecular parameters to identify those stage II patients who better benefit from adjuvant therapy.
METHODS: We examined 120 stage II colon cancer patients. Of these, 60 patients received adjuvant 5-FU chemotherapy after surgery and the other 60 did not receive therapy. Immunohistochemical (IHC) analyses were performed to evaluate the expressions of Thymidylate synthetase (TYMS), TP53 (p53), β-catenin (CTNNB1) and CD8. For TYMS, its mRNA expression levels were also investigated by real time qRT-PCR. The entire case study was characterized by the presence of a defect in the MMR (mismatch repair) system, the presence of the CpG island methylator phenotype (CIMP or CIMP-High) and for the V600E mutation in the BRAF gene. At the histo-pathological level, the depth of tumour invasion, lymphovascular invasion, invasion of large veins, host lymphocytic response and tumour border configuration were recorded.
RESULTS: The presence of the V600E mutation in the BRAF gene was a poor prognostic factor for disease free and overall survival (DFS; hazard ratio [HR], 2.57; 95% CI: 1.03 -6.37; p = 0.04 and OS; HR, 3.68; 95% CI: 1.43-9.47; p < 0.01 respectively), independently of 5-FU treatment. Adjuvant therapy significantly improved survival in patients with high TYMS levels (p = 0.04), while patients with low TYMS had a better outcome if treated by surgery alone (DFS; HR, 6.07; 95% CI, 0.82 to 44.89; p = 0.04). In patients with a defect in the MMR system (dMMR), 5-FU therapy was associated to reduced survival (DFS; HR, 37.98; 95% CI, 1.04 to 1381.31; p = 0.04), while it was beneficial for CIMP-High associated tumours (DFS; HR, 0.17; 95% CI, 0.02 to 1.13; p = 0.05).
CONCLUSIONS: Patients' characterization according to MMR status, CIMP phenotype and TYMS mRNA expression may provide a more tailored approach for adjuvant therapy in stage II colon cancer.

Conconi D, Panzeri E, Redaelli S, et al.
DNA copy number alterations and PPARG amplification in a patient with multifocal bladder urothelial carcinoma.
BMC Res Notes. 2012; 5:607 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Bladder cancer is the seventh most common cancer worldwide and over 90% are transitional cell carcinoma (TCC). At the first time of diagnosis at least 70% of TCC present as superficial bladder cancer. Because the clinical outcome of superficial bladder tumors is relatively unpredictable, there is a pressing need to identify markers that may predict tumor recurrence and progression and new treatment strategies.
CASE PRESENTATION: We present a unique case of a 67-year old male who underwent total cystectomy after repeated trans-urethral resections of the bladder for multifocal non-muscle invasive bladder cancer. The first and the third tumor were diagnosed as high grade non-infiltrating (HGNI), while the second as carcinoma in situ (CIS). We performed both array comparative genomic hybridization and a targeted chromosomal profile by UroVysion in order to detect copy number variations (CNVs) that may be involved with tumor recurrence and progression. The overall data from this study provide new evidence for the monoclonal origin of urothelial tumor multifocality as several genetic changes were found in different tumors of the same patient. From the analysis of shared CNVs two gained regions emerged at 3p25.2 and 12q23.2, including PPARG and ASCL1 genes, respectively. The copy number level of these genes would seem inversely mutually correlated and highly dependent on histological grade, because the highest level of amplification at 3p25.2 was evidenced in the two HGNI samples, while the highest level of copy number gain at 12q23.2 was reported in the CIS.
CONCLUSION: We provide new evidence on the role of PPARG in initiation and maintenance of bladder cancer. For the first time we also suggest a possible explanation for the elevated expression of PPARG in this type of tumor through a focal high level amplification at 3p25.2. Furthermore, a new gene, ASCL1, emerged as a potential candidate to assist PPARG in bladder carcinogenesis.

Mijatovic V, Iacobucci I, Sazzini M, et al.
Imputation reliability on DNA biallelic markers for drug metabolism studies.
BMC Bioinformatics. 2012; 13 Suppl 14:S7 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Imputation is a statistical process used to predict genotypes of loci not directly assayed in a sample of individuals. Our goal is to measure the performance of imputation in predicting the genotype of the best known gene polymorphisms involved in drug metabolism using a common SNP array genotyping platform generally exploited in genome wide association studies.
METHODS: Thirty-nine (39) individuals were genotyped with both Affymetrix Genome Wide Human SNP 6.0 (AFFY) and Affymetrix DMET Plus (DMET) platforms. AFFY and DMET contain nearly 900000 and 1931 markers respectively. We used a 1000 Genomes Pilot + HapMap 3 reference panel. Imputation was performed using the computer program Impute, version 2. SNPs contained in DMET, but not imputed, were analysed studying markers around their chromosome regions. The efficacy of the imputation was measured evaluating the number of successfully imputed SNPs (SSNPs).
RESULTS: The imputation predicted the genotypes of 654 SNPs not present in the AFFY array, but contained in the DMET array. Approximately 1000 SNPs were not annotated in the reference panel and therefore they could not be directly imputed. After testing three different imputed genotype calling threshold (IGCT), we observed that imputation performs at its best for IGCT value equal to 50%, with rate of SSNPs (MAF > 0.05) equal to 85%.
CONCLUSIONS: Most of the genes involved in drug metabolism can be imputed with high efficacy using standard genome-wide genotyping platforms and imputing procedures.

Dahlman KB, Parker JS, Shamu T, et al.
Modulators of prostate cancer cell proliferation and viability identified by short-hairpin RNA library screening.
PLoS One. 2012; 7(4):e34414 [PubMed] Free Access to Full Article Related Publications
There is significant need to identify novel prostate cancer drug targets because current hormone therapies eventually fail, leading to a drug-resistant and fatal disease termed castration-resistant prostate cancer. To functionally identify genes that, when silenced, decrease prostate cancer cell proliferation or induce cell death in combination with antiandrogens, we employed an RNA interference-based short hairpin RNA barcode screen in LNCaP human prostate cancer cells. We identified and validated four candidate genes (AKT1, PSMC1, STRADA, and TTK) that impaired growth when silenced in androgen receptor positive prostate cancer cells and enhanced the antiproliferative effects of antiandrogens. Inhibition of AKT with a pharmacologic inhibitor also induced apoptosis when combined with antiandrogens, consistent with recent evidence for PI3K and AR pathway crosstalk in prostate cancer cells. Recovery of hairpins targeting a known prostate cancer pathway validates the utility of shRNA library screening in prostate cancer as a broad strategy to identify new candidate drug targets.

Nelli F, Moscetti L, Natoli G, et al.
Gemcitabine and carboplatin for pretreated metastatic breast cancer: the predictive value of immunohistochemically defined subtypes.
Int J Clin Oncol. 2013; 18(2):343-9 [PubMed] Related Publications
BACKGROUND: We evaluated the efficacy of gemcitabine and carboplatin for patients affected by pretreated metastatic breast cancer. A subgroup analysis was performed to evaluate the predictive value of immunohistochemically defined breast cancer subtypes.
METHODS: We included human epidermal growth factor 2 (HER-2) negative metastatic breast cancer resistant to previous anthracycline-based and taxane-based chemotherapy, and HER-2 positive metastatic breast cancer with at least two progressions of disease during protracted trastuzumab-based therapy. Treatment consisted of gemcitabine (1000 mg/m(2) intravenous (iv) on days 1 and 8) and carboplatin (area under the curve 5 iv on day 1) applied every 3 weeks.
RESULTS: Forty-two patients were registered. Disease control was 58%, with a median time-to-progression (TTP) of 7 months (range 1-12) and a median overall survival of 10.5 months (range 1-34). Patients were grouped as triple negative (ER and PR negative, HER-2 negative), HER-2 (HER-2 positive, ER and PR negative), luminal B (ER and/or PR positive and either HER-2 positive and/or high Ki67), and luminal A (ER and/or PR positive and HER-2 negative and low Ki67). For luminal A patients, disease control was lower (luminal A 34 vs. others 67%; P = 0.02), TTP was shorter (luminal A 2.4 months vs. others 6.3 months, P = 0.015), and overall survival was shorter (luminal A 7.5 months vs. others 11.7 months, P = 0.034) than for other subtypes.
CONCLUSIONS: Gemcitabine and carboplatin are effective for pretreated patients with metastatic breast cancer. Luminal A subtype seems to fare poorly compared with other subtypes. Specific difference in gene expression might account for the different outcome.

Magistroni V, Mologni L, Sanselicio S, et al.
ERG deregulation induces PIM1 over-expression and aneuploidy in prostate epithelial cells.
PLoS One. 2011; 6(11):e28162 [PubMed] Free Access to Full Article Related Publications
The ERG gene belongs to the ETS family of transcription factors and has been found to be involved in atypical chromosomal rearrangements in several cancers. To gain insight into the oncogenic activity of ERG, we compared the gene expression profile of NIH-3T3 cells stably expressing the coding regions of the three main ERG oncogenic fusions: TMPRSS2/ERG (tERG), EWS/ERG and FUS/ERG. We found that all three ERG fusions significantly up-regulate PIM1 expression in the NIH-3T3 cell line. PIM1 is a serine/threonine kinase frequently over-expressed in cancers of haematological and epithelial origin. We show here that tERG expression induces PIM1 in the non-malignant prostate cell line RWPE-1, strengthening the relation between tERG and PIM1 up-regulation in the initial stages of prostate carcinogenesis. Silencing of tERG reversed PIM1 induction. A significant association between ERG and PIM1 expression in clinical prostate carcinoma specimens was found, suggesting that such a mechanism may be relevant in vivo. Chromatin Immunoprecipitation experiments showed that tERG directly binds to PIM1 promoter in the RWPE-1 prostate cell line, suggesting that tERG could be a direct regulator of PIM1 expression. The up-regulation of PIM1 induced by tERG over-expression significantly modified Cyclin B1 levels and increased the percentage of aneuploid cells in the RWPE-1 cell line after taxane-based treatment. Here we provide the first evidence for an ERG-mediated PIM1 up-regulation in prostate cells in vitro and in vivo, suggesting a direct effect of ERG transcriptional activity in the alteration of genetic stability.

Martini M, Vecchione L, Siena S, et al.
Targeted therapies: how personal should we go?
Nat Rev Clin Oncol. 2011; 9(2):87-97 [PubMed] Related Publications
Despite the development of drugs inhibiting the oncogenic proteins that cancer cells are dependent on, attempts to match targeted therapies to the genetic makeup of individual tumors is proving more difficult than expected. Until now, the paradigm has been a binary correlation between a mutated cancer gene and response to a given therapy. However, recent evidence indicates that different genetic alterations, such as mutations in different codons of a cancer gene, might be related to distinct sensitivity to targeted therapies. An example is the divergent effect that individual EGFR, PIK3CA and KRAS mutations might have on response or resistance to tailored drugs. Furthermore, the idea that the presence of a specific mutation translates into sensitivity or resistance to a particular drug is likely too simplistic, since it does not capture the complexity of the signaling pathways in an individual cancer. Only the overall genetic milieu (alterations in upstream and/or parallel pathways) ultimately determines the response of individual tumors to therapy. We have critically analyzed data supporting the genetic, biological and biochemical differences of individual mutations within a single cancer gene. The role of cancer mutations as predictors of sensitivity and resistance to targeted therapies is discussed, together with the implications for the 'personalized' treatment of cancer patients.

Ferruzzi P, Mennillo F, De Rosa A, et al.
In vitro and in vivo characterization of a novel Hedgehog signaling antagonist in human glioblastoma cell lines.
Int J Cancer. 2012; 131(2):E33-44 [PubMed] Related Publications
Glioblastoma multiforme (GBM) is composed of heterogeneous and genetically different cells, which are highly invasive and motile. The standard chemotherapeutic agent, temozolomide, affects GBM cell proliferation but is generally unable to prevent tumor recurrence. Hedgehog pathway activation has been reported to be relevant in GBM and different pharmacological pathway modulators have been identified. We report that by growing a commercially available recurrent GBM cell line (DBTRG-05MG) without serum and in the presence of defined growth factors; we obtained a less differentiated cell population, growing in suspension as neurospheres, in which the Hedgehog pathway is activated. Furthermore, the expression profile of Hedgehog pathway components found in DBTRG-05MG neurospheres is similar to primary stem-like cells derived from recurrent GBM patients. We report the effect of our novel specific Smoothened receptor antagonist (SEN450) on neurosphere growing cells and compared its effect to that of well known benchmark compounds. Finally, we showed that SEN450 is both antiproliferative on its own and further reduces tumor volume after temozolomide pretreatment in a mouse xenograft model using DBTRG-05MG neurosphere cells. Altogether our data indicate that the Hedgehog pathway is not irreversibly switched off in adherent cells but can be reactivated when exposed to well-defined culture conditions, thus restoring the condition observed in primary tumor-derived material, and that pharmacological modulation of this pathway can have profound influences on tumor proliferation. Therefore, pharmacological inhibition of the Hedgehog pathway is a potentially useful therapeutic approach in GBM.

Guerreiro AS, Fattet S, Kulesza DW, et al.
A sensitized RNA interference screen identifies a novel role for the PI3K p110γ isoform in medulloblastoma cell proliferation and chemoresistance.
Mol Cancer Res. 2011; 9(7):925-35 [PubMed] Related Publications
Medulloblastoma is the most common malignant brain tumor in children and is associated with a poor outcome. We were interested in gaining further insight into the potential of targeting the human kinome as a novel approach to sensitize medulloblastoma to chemotherapeutic agents. A library of small interfering RNA (siRNA) was used to downregulate the known human protein and lipid kinases in medulloblastoma cell lines. The analysis of cell proliferation, in the presence or absence of a low dose of cisplatin after siRNA transfection, identified new protein and lipid kinases involved in medulloblastoma chemoresistance. PLK1 (polo-like kinase 1) was identified as a kinase involved in proliferation in medulloblastoma cell lines. Moreover, a set of 6 genes comprising ATR, LYK5, MPP2, PIK3CG, PIK4CA, and WNK4 were identified as contributing to both cell proliferation and resistance to cisplatin treatment in medulloblastoma cells. An analysis of the expression of the 6 target genes in primary medulloblastoma tumor samples and cell lines revealed overexpression of LYK5 and PIK3CG. The results of the siRNA screen were validated by target inhibition with specific pharmacological inhibitors. A pharmacological inhibitor of p110γ (encoded by PIK3CG) impaired cell proliferation in medulloblastoma cell lines and sensitized the cells to cisplatin treatment. Together, our data show that the p110γ phosphoinositide 3-kinase isoform is a novel target for combinatorial therapies in medulloblastoma.

Risio M, Venesio T, Kolomoets E, et al.
Genetic polymorphisms of CYP17A1, vitamin D receptor and androgen receptor in Italian heredo-familial and sporadic prostate cancers.
Cancer Epidemiol. 2011; 35(4):e18-24 [PubMed] Related Publications
BACKGROUND: Searching for genetic and environmental factors predisposing to prostate cancer, common single-nucleotide polymorphisms in CYP17A1, CYP19A1, VDR genes, and the number of CAG repeats from AR were investigated in Italian heredo-familial prostate cancer (HFPC) patients controlled for dietary intake and life style habits.
METHODS: We evaluated differences between HFPC and sporadic cancers, in the pattern of common single-nucleotide polymorphisms in CYP17A1, CYP19A1, VDR genes, and the CAG repeat from AR, controlling for dietary intake and lifestyle habits in a regionwide population. Ninety-five patients with HFPC were identified and 378 sporadic prostate cancers were randomly selected as controls. Dietary intake and lifestyle habits were determined through self-administered questionnaires in all patients. Genotyping of polymorphisms for CYP17A1, CYP19A1, VDR, and the CAG repeat from AR was carried out using pyrosequencing.
RESULTS: HFPC cases were significantly younger than controls, whereas similar proportions of localized tumours, favourable histology, and abnormal prostate serum antigen levels (4-19 ng/ml) were detected in the two groups. A statistically evident gene-gene interaction was found: a 5-fold higher probability [odds ratio (OR)=4.83; 95% confidence interval (CI): 1.37-17.02] of HFPC was observed in the subgroup profiling VDR1 T/T genotypes coupled with VDR2 T/T genotype. Among nutrients, an increase in HFPC risk (OR=3.14; 95% CI: 1.12-8.81) was found only for zinc, when associated with the VDR2 T/T genotype.
CONCLUSIONS: Significant evidence for positive interactions between VDR1 and VDR2 genotypes was demonstrated, suggesting that high-risk multigenic polymorphism profiles could variously sustain HFPC tumorigenesis.

Xu X, Omelchenko T, Hall A
LKB1 tumor suppressor protein regulates actin filament assembly through Rho and its exchange factor Dbl independently of kinase activity.
BMC Cell Biol. 2010; 11:77 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Germline mutations in LKB1 result in Peutz-Jeghers Syndrome characterized by intestinal hamartomas and increased incidence of epithelial cancers. LKB1 encodes a serine/threonine kinase that plays an important role in regulating energy metabolism through the AMPK/mTOR signaling pathway. In addition, LKB1 is homologous to PAR-4, a polarity protein first described in C. elegans, while activation of LKB1 in mammalian epithelial cells induces the polarized assembly of actin filaments.
RESULTS: To explore the mechanism by which LKB1 interacts with the actin cytoskeleton, we introduced LKB1 into HeLa cells that lack endogenous LKB1. This results in activation of the small GTPase Rho and the assembly of linear actin filaments associated with focal adhesions. These effects on the actin cytoskeleton are attenuated by siRNA-mediated depletion of the guanine nucleotide exchange factor Dbl. Co-expression of the LKB1 with the adaptor protein STRAD induces actin filament puncta associated with phospho-ezrin.
CONCLUSIONS: This study reveals that LKB1 regulates the actin cytoskeleton through a Dbl/Rho pathway.

Bertotti A, Bracco C, Girolami F, et al.
Inhibition of Src impairs the growth of met-addicted gastric tumors.
Clin Cancer Res. 2010; 16(15):3933-43 [PubMed] Related Publications
PURPOSE: We examined whether inhibition of Src tyrosine kinase, a downstream effector of the MET oncogene, can hinder the malignant properties of gastric tumors dependent on Met for growth and survival.
EXPERIMENTAL DESIGN: Sensitivity to Src inhibition was determined in vitro by measuring clonogenic survival (anchorage-independent growth) and in vivo by establishing xenograft models. Four "Met-addicted" gastric carcinoma cell lines (GTL16, MKN45, HS746T, and SNU5) and three Met-independent gastric carcinoma cell lines (KATO III, AGS, and NCI-N87) were treated with the Src inhibitor saracatinib (AZD0530). In GTL16 and KATO III, Src neutralization was also achieved by dasatinib and RNA interference. The biochemical and transcriptional consequences of Src inhibition were explored using anti-phosphoprotein antibodies and oligonucleotide microarrays.
RESULTS: Inhibition of Src in Met-addicted gastric carcinoma cell lines (a) decreased the phosphorylation/activation levels of signaling intermediates involved in cell proliferation and protection from apoptosis and down-modulated the expression of several cell cycle regulators; (b) reduced anchorage-independent growth; (c) enhanced impairment of cell viability produced by Met inhibition; and (d) delayed tumorigenesis in xenotransplantation models. Immunohistochemical analysis of tumor xenograft tissues following systemic treatment with saracatinib showed a reduction of tumor cell proliferation index, increased apoptosis, and diminished phospho-focal adhesion kinase and phospho-paxillin staining. Tumor stroma parameters such as angiogenesis or inflammatory infiltration were unaffected. In clonogenic survival assays, gastric carcinoma cells without addiction to Met were less sensitive than Met-addicted cells to Src inhibition.
CONCLUSIONS: Src is as a key downstream transducer of Met-driven tumor growth. Targeting Src might provide therapeutic benefit in Met-addicted tumors.

Donada M, Bonin S, Nardon E, et al.
Thymidilate synthase expression predicts longer survival in patients with stage II colon cancer treated with 5-flurouracil independently of microsatellite instability.
J Cancer Res Clin Oncol. 2011; 137(2):201-10 [PubMed] Related Publications
BACKGROUND: 5-Fluorouracil (5-FU) is the most commonly used therapeutic agent for colon cancer treatment. Several studies have evaluated in patients with colon cancer, either the role of genes involved in the 5-FU pathway, such as thymidylate synthase (TS), thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) or the role of microsatellite instability (MSI) as prognostic or predictive markers for adjuvant chemotherapy efficacy, with discordant results. In this study we investigated the combined effect of TS, TP, DPD mRNA expression and MSI status in primary tumors of patients with colon cancer, all treated with 5-FU adjuvant therapy.
METHODS: TS, TP and DPD expression levels were investigated by real-time quantitative RT-PCR on RNA extracts from formalin-fixed and paraffin-embedded tissues of 55 patients with colon adenocarcinoma. In the same case study MSI status was assessed on DNA extracts.
RESULTS: A higher TS expression was significantly associated with a longer survival for patients with cancers of stage II (P < 0.01), but not for those with stage III (P = 0.68). In addition, in multivariate analysis, a higher TS expression was significantly associated with a decreased risk of death (HR 0.13, 95% CI 0.03-0.59, P < 0.01), while the MSI status did not have effects on patients' survival.
CONCLUSIONS: This retrospective investigation suggests that TS gene expression at mRNA level can be a useful marker of better survival in patients (especially of those with cancers of stage II) receiving 5-FU adjuvant chemotherapy, independently of the MSI status.

Begnini A, Tessari G, Turco A, et al.
PTCH1 gene haplotype association with basal cell carcinoma after transplantation.
Br J Dermatol. 2010; 163(2):364-70 [PubMed] Related Publications
BACKGROUND: Basal cell carcinoma (BCC) is 10 times more frequent in organ transplant recipients (OTRs) than in the general population. Factors in OTRs conferring increased susceptibility to BCC include ultraviolet radiation exposure, immunosuppression, viral infections such as human papillomavirus, phototype and genetic predisposition. The PTCH1 gene is a negative regulator of the hedgehog pathway, that provides mitogenic signals to basal cells in skin. PTCH1 gene mutations cause naevoid BCC syndrome, and contribute to the development of sporadic BCC and other types of cancers. Associations have been reported between PTCH1 polymorphisms and BCC susceptibility in nontransplanted individuals.
OBJECTIVES: To search for novel common polymorphisms in the proximal 5' regulatory region upstream of PTCH1 gene exon 1B, and to investigate the possible association of PTCH1 polymorphisms and haplotypes with BCC risk after organ transplantation.
METHODS: Three PTCH1 single nucleotide polymorphisms (rs2297086, rs2066836 and rs357564) were analysed by restriction fragment length polymorphism analysis in 161 northern Italian OTRs (56 BCC cases and 105 controls). Two regions of the PTCH1 gene promoter were screened by heteroduplex analysis in 30 cases and 30 controls.
RESULTS: Single locus analysis showed no significant association. Haplotype T(1686)-T(3944) appeared to confer a significantly higher risk for BCC development (odds ratio 2.98, 95% confidence interval 2.55-3.48; P = 0.001). Two novel rare polymorphisms were identified at positions 176 and 179 of the 5'UTR. Two novel alleles of the -4 (CGG)(n) microsatellite were identified. No association of this microsatellite with BCC was observed.
CONCLUSIONS: Haplotypes containing T(1686)-T(3944) alleles were shown to be associated with an increased BCC risk in our study population. These data appear to be of great interest for further investigations in a larger group of transplant individuals. Our results do not support the hypothesis that common polymorphisms in the proximal 5' regulatory region of the PTCH1 gene could represent an important risk factor for BCC after organ transplantation.

Narbonne P, Hyenne V, Li S, et al.
Differential requirements for STRAD in LKB1-dependent functions in C. elegans.
Development. 2010; 137(4):661-70 [PubMed] Related Publications
The protein kinase LKB1 is a crucial regulator of cell growth/proliferation and cell polarity and is the causative gene in the cancer-predisposing disease Peutz-Jeghers syndrome (PJS). The activity of LKB1 is greatly enhanced following its association with the Ste20-like adapter protein STRAD. Unlike LKB1 however, mutations in STRAD have not been identified in PJS patients and thus, the key tumour suppressive role(s) of LKB1 might be STRAD independent. Here, we report that Caenorhabditis elegans strd-1/STRAD mutants recapitulate many phenotypes typical of par-4/LKB1 loss of function, showing defects during early embryonic and dauer development. Interestingly, although the growth/proliferation defects in severe par-4 and strd-1 mutant dauers are comparable, strd-1 mutant embryos do not share the polarity defects of par-4 embryos. We demonstrate that most of par-4-dependent regulation of germline stem cell (GSC) quiescence occurs through AMPK, whereby PAR-4 requires STRD-1 to phosphorylate and activate AMPK. Consistent with this, even though AMPK plays a major role in the regulation of cell proliferation, like strd-1 it does not affect embryonic polarity. Instead, we found that the PAR-4-mediated phosphorylation of polarity regulators such as PAR-1 and MEX-5 in the early embryo occurs in the absence of STRD-1. Thus, PAR-4 requires STRD-1 to phosphorylate AMPK to regulate cell growth/proliferation under reduced insulin signalling conditions, whereas PAR-4 can promote phosphorylation of key proteins, including PAR-1 and MEX-5, to specify early embryonic polarity independently of STRD-1. Our results therefore identify a key strd-1/STRAD-independent function of par-4/LKB1 in polarity establishment that is likely to be important for tumour suppression in humans.

Valensin S, Ghiron C, Lamanna C, et al.
KIF11 inhibition for glioblastoma treatment: reason to hope or a struggle with the brain?
BMC Cancer. 2009; 9:196 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Glioblastomas (GBM) are typically comprised of morphologically diverse cells. Despite current advances in therapy, including surgical resection followed by radiation and chemotherapy, the prognosis for patients with GBM remains poor. Unfortunately, most patients die within 2 years of diagnosis of their disease. Molecular abnormalities vary among individual patients and also within each tumor. Indeed, one of the distinguishing features of GBM is its marked genetic heterogeneity. Due to the brain location of the tumor, the potential target inhibition for anticancer therapy must exhibit a manageable neurotoxicity profile in the concentration range in which the compounds show anti-proliferative activity.Kinesin KIF11 inhibition by small molecules such as Monastrol or Ispinesib is currently under investigation in the field of malignant tumors. In the current study we have assessed the relevance of the anti-mitotic Kinesin-like protein KIF11 in human GBM cell-lines.
RESULTS: In this study the target was validated using a set of well characterised and potentially specific small molecule inhibitors of KIF11: an ispinesib analog, Monastrol, a Merck compound and 3 simplified derivatives of the Merck compound. Following an in silico selection, those compounds predicted to bear a favorable BBB permeation profile were assessed for their phenotypic effect on cell lines derived both from primary (U87MG) as well as treated (DBTRG-05-MG) glioblastomas. For some compounds, these data could be compared to their effect on normal human astrocytes, as well as their neurotoxicity on primary rat cortical neurons. The ispinesib analogue 1 showed an anti-proliferative effect on GBM cell lines by blocking them in the G2/M phase in a concentration range which was shown to be harmless to primary rat cortical neurons. Furthermore, ispinesib analog increased caspase 3/7-induced apoptosis in U87MG cells.
CONCLUSION: In the area of cell cycle inhibition, KIF11 is critical for proper spindle assembly and represents an attractive anticancer target. Our results suggest that KIF11 inhibitors, when able to permeate the blood-brain-barrier, could represent an interesting class of anticancer drugs with low neurotoxic effects in the treatment of brain tumors.

Donadelli M, Dalla Pozza E, Scupoli MT, et al.
Intracellular zinc increase inhibits p53(-/-) pancreatic adenocarcinoma cell growth by ROS/AIF-mediated apoptosis.
Biochim Biophys Acta. 2009; 1793(2):273-80 [PubMed] Related Publications
We show that treatment with non-toxic doses of zinc in association to the ionophore compound pyrrolidine dithiocarbamate (PDTC) inhibits p53(-/-) pancreatic cancer cell growth much more efficiently than gemcitabine, the gold standard chemotherapeutic agent for pancreatic cancer. Both the metal chelator N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine and the radical scavenger N-acetyl-l-cysteine are able to recover cell growth inhibition by Zn/PDTC, demonstrating that this effect depends on the increased levels of intracellular zinc and of reactive oxygen species (ROS). Zn/PDTC treatment induces a strong apoptotic cell death that is associated to ROS-dependent nuclear translocation of the mitochondrial factor AIF, but not to the regulation of apoptotic genes and caspase activation. Primary fibroblasts are more resistant than pancreatic cancer cells to Zn/PDTC treatment and exhibit a lower basal and Zn/PDTC-induced enhancement of intracellular zinc. We show that Zn/PDTC induces p53 proteasomal degradation and that the proteasome inhibitor MG132 further increases fibroblast growth inhibition by Zn/PDTC, suggesting that p53 degradation plays an important role in fibroblast resistance to Zn/PDTC.

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