"The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway." (Source: MeSH)
Figure: An overview of major signal transduction pathways
Source: https://en.wikipedia.org/wiki/File:Signal_transduction_pathways.svg (License: CC BY-SA 3.0)
Introduction to Cancer Biology (Part 1): Abnormal Signal Transduction
mechanismsinmedicine.com Educational animation which explains the mechanism of abnormal signal transduction resulting in uncontrolled cell proliferation. This animation also provides an overview of the potential targets of anticancer therapies.
This list of publications is regularly updated (Source: PubMed).
Goschzik T, Gessi M, Denkhaus D, Pietsch T PTEN mutations and activation of the PI3K/Akt/mTOR signaling pathway in papillary tumors of the pineal region. J Neuropathol Exp Neurol. 2014; 73(8):747-51 [PubMed] Related Publications
Papillary tumors of the pineal region (PTPR) are recognized as a distinct entity in the World Health Organization classification of CNS tumors. Papillary tumors of the pineal region frequently show loss of chromosome 10, but no studies have investigated possible target genes on this chromosome. Chromosome 10 harbors the PTEN (phosphatase and tensin homolog) gene, the inactivation of which, by mutation or epigenetic silencing, has been observed in different brain tumors, including high-grade gliomas. In this study, we investigated copy number changes by molecular inversion probe (MIP) analysis and the mutational status of PTEN in 13 PTPR by direct sequencing. MIP analysis of 5 PTPR showed chromosome 10 loss in all cases. In addition, there were losses of chromosomes 3, 14, 22, and X, and gains of whole chromosomes 8, 9, and 12 in more than 1 case. One case had a homozygous PTEN deletion; and 2 point mutations in exon 7 of PTEN (G251D and Q261stop) were found. Immunohistochemistry revealed decrease or loss of the PTEN protein and increased expression of p-Akt and p-S6. These results indicated that PTEN mutations and activation of the PI3K/Akt/mTOR signaling pathway may play a role in the biology of PTPR. This evidence may lead to the possible use of PI3K/Akt/mTOR inhibitors in therapy for patients with PTPR.
In this issue of Blood, Mraz et al show that microRNA-150 (miR-150) is the most abundantly expressed miR in chronic lymphocytic leukemia (CLL) and affects the threshold for B-cell receptor (BCR) signaling by repressing expression levels of GAB1 and FOXP1. This functional link might explain the described association between expression levels of miR-150 and prognosis.
Yi YS, Baek KS, Cho JY L1 cell adhesion molecule induces melanoma cell motility by activation of mitogen-activated protein kinase pathways. Pharmazie. 2014; 69(6):461-7 [PubMed] Related Publications
L1 cell adhesion molecule (L1CAM) is highly expressed in various types of cancer cells and has been implicated in the control of cell proliferation and motility. Recently, L1CAM was reported to induce the motility of melanoma cells, but the mechanism of this induction remains poorly understood. In this study, we investigated the molecular mechanisms by which L1CAM induces the motility of melanoma cells. Unlike other types of cancer cells, B16F10 melanoma cells highly expressed L1CAM at both the RNA and protein levels, and the expression of L1CAM induced AP-1 activity. In accordance to AP-1 activation, MAPK signaling pathways were activated by L1CAM. Inhibition of L1CAM expression by L1CAM-specific siRNA suppressed the activation of MAPKs such as ERK and p38. However, no significant change was observed in JNK activation. As expected, upstream MAP2K, MKK3/6, MAP3K, and TAK1 were also deactivated by the inhibition of L1CAM expression. L1CAM induced the motility of B16F10 cells. Inhibition of L1CAM expression suppressed migration and invasion of B16F10 cells, but no suppressive effect was observed on their proliferation and anti-apoptotic resistance. Treatment of B16F10 cells with U0126, an ERK inhibitor, or SB203580, a p38 inhibitor, suppressed the migration and invasion abilities of B16F10 cells. Taken together, our results suggest that L1CAM induces the motility of B16F10 melanoma cells via the activation of MAPK pathways. This finding provides a more detailed molecular mechanism of L1CAM-mediated induction of melanoma cell motility.
Fu W, Asp P, Canter B, Dynlacht BD Primary cilia control hedgehog signaling during muscle differentiation and are deregulated in rhabdomyosarcoma. Proc Natl Acad Sci U S A. 2014; 111(25):9151-6 [PubMed] Article available free on PMC after 24/12/2014 Related Publications
The primary cilium acts as a cellular antenna, transducing diverse signaling pathways, and recent evidence suggests that primary cilia are important in development and cancer. However, a role for cilia in normal muscle development and rhabdomyosarcoma (RMS) has not been explored. Here we implicate primary cilia in proliferation, hedgehog (Hh) signaling, and differentiation of skeletal muscle cells. Cilia and Hh signaling are highly dynamic during the differentiation of myoblasts. We show that cilia are assembled during the initial stages of myogenic differentiation but disappear as cells progress through myogenesis, concomitant with the destruction of proteins critical for cilia assembly and shortly after the Hh effector, Gli3, leaves the cilium. Importantly, we show that ablation of primary cilia strongly suppresses Hh signaling and myogenic differentiation while enhancing proliferation. Interestingly, our data further indicate that both cilia assembly and Hh signaling are deregulated in RMS, and cilia respond to Hh ligand in certain subsets of RMS cells but not others. Together, these findings provide evidence for an essential role for both primary cilia assembly and disassembly in the control of Hh signaling and early differentiation in muscle cells. We suggest that the temporally orchestrated destruction of centrosomal and ciliary proteins is a necessary antecedent for removal of the primary cilium and cessation of Hh signaling during myogenic differentiation. Additionally, our results further stratify RMS populations and highlight cilia assembly and disassembly as potential RMS drug targets.
Quan P, Moinfar F, Kufferath I, et al. Effects of targeting endometrial stromal sarcoma cells via histone deacetylase and PI3K/AKT/mTOR signaling. Anticancer Res. 2014; 34(6):2883-97 [PubMed] Related Publications
AIM: Endometrial stromal sarcoma (ESS) is a rare gynecological mesenchymal malignancy with only few therapeutic options. This study aimed to investigate the efficacy of the histone deacetylase (HDAC) inhibitor suberanilohydroxamic acid (SAHA) combined with inhibitors of the phosphoinositid-3-Kinase (PI3K) pathway in ESS therapy. MATERIALS AND METHODS: The effects of SAHA combined with inhibitor of PI3K (LY294002, LY), mammalian target of rapamycin mTOR (rapamycin), and their combination on cell growth and the PI3K pathway in two ESS cell lines (ESS-1 and MES-SA) and one non-neoplastic cell line HESC, were investigated. RESULTS: SAHA reduced growth of the three cell lines by inhibiting protein kinase B AKT and mTOR/p70S6K cascade activation. SAHA combined with LY or rapamycin, or both, synergistically reduced p-p70S6K and p-4E-BP1 levels. SAHA combined with LY and rapamycin led to the strongest growth inhibition and slowest growth recovery among the combination treatments. CONCLUSION: SAHA combined with inhibition of PI3K and mTOR could represent an efficient therapy option for patients with ESS.
Häggström J, Cipriano M, Forshell LP, et al. Potential upstream regulators of cannabinoid receptor 1 signaling in prostate cancer: a Bayesian network analysis of data from a tissue microarray. Prostate. 2014; 74(11):1107-17 [PubMed] Article available free on PMC after 24/12/2014 Related Publications
BACKGROUND: The endocannabinoid system regulates cancer cell proliferation, and in prostate cancer a high cannabinoid CB1 receptor expression is associated with a poor prognosis. Down-stream mediators of CB1 receptor signaling in prostate cancer are known, but information on potential upstream regulators is lacking. RESULTS: Data from a well-characterized tumor tissue microarray were used for a Bayesian network analysis using the max-min hill-climbing method. In non-malignant tissue samples, a directionality of pEGFR (the phosphorylated form of the epidermal growth factor receptor) → CB1 receptors were found regardless as to whether the endocannabinoid metabolizing enzyme fatty acid amide hydrolase (FAAH) was included as a parameter. A similar result was found in the tumor tissue, but only when FAAH was included in the analysis. A second regulatory pathway, from the growth factor receptor ErbB2 → FAAH was also identified in the tumor samples. Transfection of AT1 prostate cancer cells with CB1 receptors induced a sensitivity to the growth-inhibiting effects of the CB receptor agonist CP55,940. The sensitivity was not dependent upon the level of receptor expression. Thus a high CB1 receptor expression alone does not drive the cells towards a survival phenotype in the presence of a CB receptor agonist. CONCLUSIONS: The data identify two potential regulators of the endocannabinoid system in prostate cancer and allow the construction of a model of a dysregulated endocannabinoid signaling network in this tumor. Further studies should be designed to test the veracity of the predictions of the network analysis in prostate cancer and other solid tumors.
Kang S, Zhao Y, Hu K, et al. miR-124 exhibits antiproliferative and antiaggressive effects on prostate cancer cells through PACE4 pathway. Prostate. 2014; 74(11):1095-106 [PubMed] Related Publications
INTRODUCTION: PACE4 plays an important role in prostate cancer (PCa) proliferation and aggression, which might provide a useful target against prostate cancer. In this study, we had strived to find some key miRNAs to decrease malignancy and invasiveness of PCa through regulating PACE4 expression. METHODS: Clinically pathological analysis of immunohistochemistry/in situ hybridization was carried out to detect the relationship between PACE4 expression/miRNAs and the malignancy of prostate mass. Prostate cell lines (DU145, C4-2, and BPH-1) were cultured for growth curve, immunocytochemistry analysis, colony formation, Matrigel invasion, and transcriptional/translational expression assay of PACE4-related signaling molecules for confirming the relationship. MiRNAs targeting PACE4 were predicted, validated and further-corroborated using bio-software, real-time PCR, luciferase reporter assay and transfection of miRNA mimics and inhibitor. RESULTS: It was suggested that PACE4 might reflect the pathological malignancy of prostate lesion from pathology analysis. Moreover, DU145 cells, the highest PACE4-level and related TF expression indicated of the strongest malignancy and invasiveness. It was significantly found that miR-124 was presented with the biggest odd to target PACE4-3'UTR, the capability of decreasing PACE expression and slowing down cell growth and cell invasion. CONCLUSIONS: It was clear that PACE4 level was closely associated with malignancy and invasiveness of PCa in vivo or in vitro MiR-124, played a crucial role inhibiting PACE4 transcription thus exhibiting obvious effects of antiproliferation and antiaggression of PCa.
Moshfegh Y, Bravo-Cordero JJ, Miskolci V, et al. A Trio-Rac1-Pak1 signalling axis drives invadopodia disassembly. Nat Cell Biol. 2014; 16(6):574-86 [PubMed] Article available free on PMC after 01/12/2014 Related Publications
Rho family GTPases control cell migration and participate in the regulation of cancer metastasis. Invadopodia, associated with invasive tumour cells, are crucial for cellular invasion and metastasis. To study Rac1 GTPase in invadopodia dynamics, we developed a genetically encoded, single-chain Rac1 fluorescence resonance energy (FRET) transfer biosensor. The biosensor shows Rac1 activity exclusion from the core of invadopodia, and higher activity when invadopodia disappear, suggesting that reduced Rac1 activity is necessary for their stability, and Rac1 activation is involved in disassembly. Photoactivating Rac1 at invadopodia confirmed this previously unknown Rac1 function. We describe here an invadopodia disassembly model, where a signalling axis involving TrioGEF, Rac1, Pak1, and phosphorylation of cortactin, causes invadopodia dissolution. This mechanism is critical for the proper turnover of invasive structures during tumour cell invasion, where a balance of proteolytic activity and locomotory protrusions must be carefully coordinated to achieve a maximally invasive phenotype.
Holmström KM, Finkel T Cellular mechanisms and physiological consequences of redox-dependent signalling. Nat Rev Mol Cell Biol. 2014; 15(6):411-21 [PubMed] Related Publications
Reactive oxygen species (ROS), which were originally characterized in terms of their harmful effects on cells and invading microorganisms, are increasingly implicated in various cell fate decisions and signal transduction pathways. The mechanism involved in ROS-dependent signalling involves the reversible oxidation and reduction of specific amino acids, with crucial reactive Cys residues being the most frequent target. In this Review, we discuss the sources of ROS within cells and what is known regarding how intracellular oxidant levels are regulated. We further discuss the recent observations that reduction-oxidation (redox)-dependent regulation has a crucial role in an ever-widening range of biological activities - from immune function to stem cell self-renewal, and from tumorigenesis to ageing.
Li L, Wang M, Yu G, et al. Overactivated neddylation pathway as a therapeutic target in lung cancer. J Natl Cancer Inst. 2014; 106(6):dju083 [PubMed] Related Publications
BACKGROUND: A number of oncoproteins and tumor suppressors are known to be neddylated, but whether the neddylation pathway is entirely activated in human cancer remains unexplored. METHODS: NEDD8-activating enzyme (NAE) (E1) and NEDD8-conjugating enzyme (E2) expression and global-protein neddylation were examined by immunohistochemistry, immunoblotting, and real-time polymerase chain reaction analysis. Cell proliferation, clonogenic survival, migration, and motility in vitro, as well as tumor formation and metastasis in vivo, were determined upon neddylation inhibition by MLN4924, an investigational NEDD8-activating enzyme inhibitor. Survival was analyzed with Kaplan-Meier methods and compared by the log-rank test. All statistical tests were two-sided. RESULTS: The entire neddylation pathway, including NEDD8-activating enzyme E1, NEDD8-conjugating enzyme E2, and global-protein neddylation, is overactivated in both lung adenocarcinoma and squamous-cell carcinoma. Compared with lung adenocarcinoma patients with low expression, those with high expression had worse overall survival (NEDD8-activating enzyme E1 subunit 1 [NAE1]: hazard ratio [HR] = 2.07, 95% confidence interval [CI] = 0.95 to 4.52, P = .07; ubiquitin-conjugating enzyme E2M (UBC12): HR = 13.26, 95% CI = 1.77 to 99.35, P = .01; global protein neddylation: HR = 3.74, 95% CI = 1.65 to 8.47, P = .002). Moreover, inhibition of neddylation by the NAE inhibitor MLN4924 statistically significantly suppressed proliferation, survival, migration, and motility of lung cancer cells in vitro and tumor formation and metastasis in vivo. At the molecular level, MLN4924 inactivated Cullin-RING E3 ligases, led to accumulation of tumor-suppressive Cullin-RING E3 ligase substrates and induced phorbol-12-myristate-13-acetate-induced protein 1 (NOXA)-dependent apoptosis or cellular senescence. CONCLUSIONS: Our study highlights the overactivated neddylation pathway in lung cancer development and as a promising therapeutic target.
Lupardus PJ, Ultsch M, Wallweber H, et al. Structure of the pseudokinase-kinase domains from protein kinase TYK2 reveals a mechanism for Janus kinase (JAK) autoinhibition. Proc Natl Acad Sci U S A. 2014; 111(22):8025-30 [PubMed] Article available free on PMC after 03/12/2014 Related Publications
Janus kinases (JAKs) are receptor-associated multidomain tyrosine kinases that act downstream of many cytokines and interferons. JAK kinase activity is regulated by the adjacent pseudokinase domain via an unknown mechanism. Here, we report the 2.8-Å structure of the two-domain pseudokinase-kinase module from the JAK family member TYK2 in its autoinhibited form. We find that the pseudokinase and kinase interact near the kinase active site and that most reported mutations in cancer-associated JAK alleles cluster in or near this interface. Mutation of residues near the TYK2 interface that are analogous to those in cancer-associated JAK alleles, including the V617F and "exon 12" JAK2 mutations, results in increased kinase activity in vitro. These data indicate that JAK pseudokinases are autoinhibitory domains that hold the kinase domain inactive until receptor dimerization stimulates transition to an active state.
Zhang S, Yu M, Deng H, et al. Polyclonal rabbit anti-human ovarian cancer globulins inhibit tumor growth through apoptosis involving the caspase signaling. Sci Rep. 2014; 4:4984 [PubMed] Article available free on PMC after 03/12/2014 Related Publications
Most women with ovarian cancer are diagnosed at an advanced stage and there are few therapeutic options. Recently, monoclonal antibody therapies have had limited success, thus more effective antibodies are needed to improve long-term survival. In this report, we prepared polyclonal rabbit anti-ovarian cancer antibody (Poly Ab) by immunizing rabbits with the human ovarian cancer cell line SKOV3. The Poly Ab bound to SKOV3 and inhibited the cancer cells proliferation. Western blot analysis was conducted, which indicated that Poly Ab inhibited cancer cells through apoptosis involving the caspase signaling pathway including caspase-3 and caspase-9. Finally, compared with the control antibody, administration of Poly Ab reached 64% and 72% tumor inhibition in the subcutaneous and intraperitoneal xenograft mouse model, respectively. Our findings suggest that Poly Ab is an effective agent for apoptosis induction and may be useful as a safe anticancer agent for ovarian cancer therapy.
This Opinion article discusses emerging evidence of direct contributions of nicotine to cancer onset and growth. The list of cancers reportedly connected to nicotine is expanding and presently includes small-cell and non-small-cell lung carcinomas, as well as head and neck, gastric, pancreatic, gallbladder, liver, colon, breast, cervical, urinary bladder and kidney cancers. The mutagenic and tumour-promoting activities of nicotine may result from its ability to damage the genome, disrupt cellular metabolic processes, and facilitate growth and spreading of transformed cells. The nicotinic acetylcholine receptors (nAChRs), which are activated by nicotine, can activate several signalling pathways that can have tumorigenic effects, and these receptors might be able to be targeted for cancer therapy or prevention. There is also growing evidence that the unique genetic makeup of an individual, such as polymorphisms in genes encoding nAChR subunits, might influence the susceptibility of that individual to the pathobiological effects of nicotine. The emerging knowledge about the carcinogenic mechanisms of nicotine action should be considered during the evaluation of regulations on nicotine product manufacturing, distribution and marketing.
Cao Y, Lindström S, Schumacher F, et al. Insulin-like growth factor pathway genetic polymorphisms, circulating IGF1 and IGFBP3, and prostate cancer survival. J Natl Cancer Inst. 2014; 106(6):dju085 [PubMed] Article available free on PMC after 01/06/2015 Related Publications
BACKGROUND: The insulin-like growth factor (IGF) signaling pathway has been implicated in prostate cancer (PCa) initiation, but its role in progression remains unknown. METHODS: Among 5887 PCa patients (704 PCa deaths) of European ancestry from seven cohorts in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium, we conducted Cox kernel machine pathway analysis to evaluate whether 530 tagging single nucleotide polymorphisms (SNPs) in 26 IGF pathway-related genes were collectively associated with PCa mortality. We also conducted SNP-specific analysis using stratified Cox models adjusting for multiple testing. In 2424 patients (313 PCa deaths), we evaluated the association of prediagnostic circulating IGF1 and IGFBP3 levels and PCa mortality. All statistical tests were two-sided. RESULTS: The IGF signaling pathway was associated with PCa mortality (P = .03), and IGF2-AS and SSTR2 were the main contributors (both P = .04). In SNP-specific analysis, 36 SNPs were associated with PCa mortality with P trend less than .05, but only three SNPs in the IGF2-AS remained statistically significant after gene-based corrections. Two were in linkage disequilibrium (r 2 = 1 for rs1004446 and rs3741211), whereas the third, rs4366464, was independent (r 2 = 0.03). The hazard ratios (HRs) per each additional risk allele were 1.19 (95% confidence interval [CI] = 1.06 to 1.34; P trend = .003) for rs3741211 and 1.44 (95% CI = 1.20 to 1.73; P trend < .001) for rs4366464. rs4366464 remained statistically significant after correction for all SNPs (P trend.corr = .04). Prediagnostic IGF1 (HRhighest vs lowest quartile = 0.71; 95% CI = 0.48 to 1.04) and IGFBP3 (HR = 0.93; 95% CI = 0.65 to 1.34) levels were not associated with PCa mortality. CONCLUSIONS: The IGF signaling pathway, primarily IGF2-AS and SSTR2 genes, may be important in PCa survival.
Sun T, Co NN, Wong N PFTK1 interacts with cyclin Y to activate non-canonical Wnt signaling in hepatocellular carcinoma. Biochem Biophys Res Commun. 2014; 449(1):163-8 [PubMed] Related Publications
PFTK1 is a Cdc2-related protein kinase that is frequently upregulated in human hepatocellular carcinoma (HCC) where it correlates with metastatic features and motile phenotypes. To understand the modulated pathway underlining the PFTK1 action, here we show a physical interaction between PFTK1 and cyclin Y (CCNY) in promoting noncanonical Wnt signaling. In HCC cells, we found PFTK1 forms a direct complex with CCNY, and together readily upregulate key components of Wnt signaling (Dvl2 and Naked1). Exogenous expression of PFTK1 and CCNY activated Rho GTPases, which are known targets of the noncanonical path. In line with Rho GTPases activation, we also found marked actin polymerizations in cells with PFTK1-CCNY co-expressions. Our findings highlight a PFTK1-CCNY complex in activating noncanonical Wnt signaling in HCC cells.
Xie Q, Zhou Y, Lan G, et al. Sensitization of cancer cells to radiation by selenadiazole derivatives by regulation of ROS-mediated DNA damage and ERK and AKT pathways. Biochem Biophys Res Commun. 2014; 449(1):88-93 [PubMed] Related Publications
X-ray-based radiotherapy represents one of the most effective ways in treating human cancers. However, radioresistance and side effect remain as the most challenging issue. This study describes the design and application of novel selenadiazole derivatives as radiotherapy sensitizers to enhance X-ray-induced inhibitory effects on A375 human melanoma and Hela human cervical carcinoma cells. The results showed that, pretreatment of the cells with selenadiazole derivatives dramatically enhance X-ray-induced growth inhibition and colony formation. Flow cytometry analysis indicates that the sensitization by selenadiazole derivatives was mainly caused by induction of G2/M cell cycle arrest. Results of Western blotting demonstrated that the combined treatment-induced A375 cells growth inhibition was achieved by triggering reactive oxygen species-mediated DNA damage involving inactivation of AKT and MAPKs. Further investigation revealed that selenadiazole derivative in combination with X-ray could synergistically inhibit the activity of thioredoxin reductase-1 in A375 cells. Taken together, these results suggest that selenadiazole derivatives can act as novel radiosensitizer with potential application in combating human cancers.
García-Pérez AI, Galeano E, Nieto E, et al. Dequalinium induces cytotoxicity in human leukemia NB4 cells by downregulation of Raf/MEK/ERK and PI3K/Akt signaling pathways and potentiation of specific inhibitors of these pathways. Leuk Res. 2014; 38(7):795-803 [PubMed] Related Publications
Delocalized lipophilic cation dequalinium (DQA) selectively accumulates in mitochondria and displays anticancer activity in different malignancies. Our previous studies indicate a DQA-induced cytotoxicity in human acute promyelocytic leukemia NB4 cells by early disturbance in mitochondrial function and oxidative stress. This study shows the ability of DQA to downregulate Raf/MEK/ERK1/2 and PI3K/Akt signaling pathways in NB4 cells which leads to cell death by apoptosis and/or necrosis. Moreover, DQA potentiates the action of specific inhibitors of these pathways. These DQA effects could be mediated by redox regulation of Akt. Our results contribute to a better understanding of the cytotoxic DQA mechanism on leukemia cells and encourage the performance of further studies in combination with other agents such as kinase inhibitors for improving the efficacy of therapies against acute promyelocytic leukemia.
Song X, Wang Y, Du H, et al. Overexpression of HepaCAM inhibits cell viability and motility through suppressing nucleus translocation of androgen receptor and ERK signaling in prostate cancer. Prostate. 2014; 74(10):1023-33 [PubMed] Related Publications
BACKGROUND: HepaCAM is suppressed in a variety of human cancers, and involved in cell adhesion, growth, migration, invasion, and survival. However, the expression and function of HepaCAM in prostate cancer are still unknown. METHODS: HepaCAM expression has been detected by RT-PCR, Western blotting and immunohistochemistry staining in prostate cell lines RWPE-1, LNCap, DU145, PC3, and in 75 human prostate tissue specimens, respectively. Meanwhile, the cell proliferation ability was detected by WST-8 assay. The role of HepaCAM in prostate cancer cell migration and invasion was examined by wound healing and transwell assay. And flow cytometry was used to observe the apoptosis of prostate cancer cells. Then we detected changes of Androgen Receptor translocation and ERK signaling using immunofluorescence staining and western blot after overexpression of HepaCAM. RESULTS: The HepaCAM expression was significantly down-regulated in prostate cancer tissues and undetected in prostate cancer cells. However, the low HepaCAM expression was not statistically associated with clinicopathological characteristics of prostate cancer. Overexpression of HepaCAM in prostate cancer cells decreased the cell proliferation, migration and invasion, and induced the cell apoptosis. Meanwhile, HepaCAM prevented the androgen receptor translocation from the cytoplasm to the nucleus and down-regulated the MAPK/ERK signaling. CONCLUSION: Our results suggested that HepaCAM acted as a tumor suppressor in prostate cancer. HepaCAM inhibited cell viability and motility which might be through suppressing the nuclear translocation of Androgen Receptor and down-regulating the ERK signaling. Therefore, it was indicated that HepaCAM may be a potential therapeutic target for prostate cancer.
Pandi NS, Manimuthu M, Harunipriya P, et al. In silico analysis of expression pattern of a Wnt/β-catenin responsive gene ANLN in gastric cancer. Gene. 2014; 545(1):23-9 [PubMed] Related Publications
Actin-binding protein anillin (ANLN) is primarily involved in the cytokinesis and known to be dysregulated in many cancers including gastric cancer (GC). However, the regulation and clinical significance of ANLN in GC are far less clear. In the present study, we aimed to investigate the clinical significance and possible regulators of ANLN in GC. We have identified the Wnt/β-catenin associated regulation of ANLN by analyzing the in vitro perturbed β-catenin mRNA expression profiles. Investigating the gastric tumors from publicly available genome-wide mRNA expression profiles, we have identified the over expression of ANLN in gastric tumors. Association between ANLN expression and clinical characteristics of GC showed elevated expression in intestinal type GC. Performing a single sample prediction method across GC mRNA expression profiles, we have identified the over expression of ANLN in proliferative type gastric tumors compared to the invasive and metabolic type gastric tumors. In silico pathway prediction analysis revealed the association between Wnt/β-catenin signaling and ANLN expression in gastric tumors. Our results highlight that expression of a Wnt/β-catenin responsive gene ANLN in GC is a molecular predictor of intestinal and proliferative type gastric tumors.
Fu HL, Ma Y, Lu LG, et al. TET1 exerts its tumor suppressor function by interacting with p53-EZH2 pathway in gastric cancer. J Biomed Nanotechnol. 2014; 10(7):1217-30 [PubMed] Related Publications
TET1 protein is reported to suppress cancer invasion and metastasis in prostate and breast cancer while EZH2, a polycomb group protein, has been identified as an oncogene in many types of cancers including gastric cancer. Here we report that there is an inverse relation of the expression pattern of TET1 and EZH2 in both normal gastric mucosa and gastric cancer. In gastric mucosa, EZH2 is selectively expressed in the proliferating neck cells while TET1 and 5-hydroxymethyl-cytosine (5-hmc) exhibit very low expression in the neck cells. In contrast, TET1 and 5-hmc expression is high in gastric glandular epithelium while EZH2 expression is absent in this cell population. On the other hand, in proliferating Ki67-positive gastric cancer cells, EZH2 is highly expressed while TET1 and 5-hmc expression is significantly down-regulated. When the mouse homologue of human TET1 protein Tet1 is overexpressed in a gastric cancer cell line MGC-803, we observed the dramatically down-regulation of EZH2 in one-third of the Tet1 overexpressed cells. In addition, Tet1 overexpressing cells also lost the H3K27 trimethylation mark and the cell proliferation protein Ki67. Furthermore, Tet1 overexpression induced p53 tumor suppressor protein. The increase of p53 protein level is accompanied by the phosphorylation of p53 by activated DNA-PK. Together, these results suggested a mechanism by which TET1 suppresses cancer formation by coupling DNA demethylation with DNA-PK activation of p53 and suppression of oncogenic protein EZH2. Conversely, loss of TET1 and 5-hmc expression might contribute to EZH2 up-regulation during gastric cancer development.
Chaturvedi P, Gilkes DM, Takano N, Semenza GL Hypoxia-inducible factor-dependent signaling between triple-negative breast cancer cells and mesenchymal stem cells promotes macrophage recruitment. Proc Natl Acad Sci U S A. 2014; 111(20):E2120-9 [PubMed] Article available free on PMC after 20/11/2014 Related Publications
Intratumoral hypoxia induces the recruitment of stromal cells, such as macrophages and mesenchymal stem cells (MSCs), which stimulate invasion and metastasis by breast cancer cells (BCCs). Production of macrophage colony-stimulating factor 1 (CSF1) by BCCs is required for macrophage recruitment, but the mechanisms underlying CSF1 expression have not been delineated. Triple-negative breast cancers have increased expression of genes regulated by hypoxia-inducible factors (HIFs). In this study, we delineate two feed-forward signaling loops between human MDA-MB-231 triple-negative BCCs and human MSCs that drive stromal cell recruitment to primary breast tumors. The first loop, in which BCCs secrete chemokine (C-X-C motif) ligand 16 (CXCL16) that binds to C-X-C chemokine receptor type 6 (CXCR6) on MSCs and MSCs secrete chemokine CXCL10 that binds to receptor CXCR3 on BCCs, drives recruitment of MSCs. The second loop, in which MSCs secrete chemokine (C-C motif) ligand 5 that binds to C-C chemokine receptor type 5 on BCCs and BCCs secrete cytokine CSF1 that binds to the CSF1 receptor on MSCs, drives recruitment of tumor-associated macrophages and myeloid-derived suppressor cells. These two signaling loops operate independent of each other, but both are dependent on the transcriptional activity of HIFs, with hypoxia serving as a pathophysiological signal that synergizes with chemokine signals from MSCs to trigger CSF1 gene transcription in triple-negative BCCs.
Peiffer L, Poll-Wolbeck SJ, Flamme H, et al. Trichostatin A effectively induces apoptosis in chronic lymphocytic leukemia cells via inhibition of Wnt signaling and histone deacetylation. J Cancer Res Clin Oncol. 2014; 140(8):1283-93 [PubMed] Related Publications
BACKGROUND: The ontogenetic Wnt pathway shows almost no activity in adult tissues. In contrast, chronic lymphocytic leukemia (CLL) cells show constitutionally active Wnt signaling, which is associated with upregulated levels of pathway members such as Wnt3 and lymphoid enhancer-binding factor-1. Functionally, this results in increased resistance to apoptosis. We therefore assumed that targeting members of the pathway could reveal new therapeutic options for the treatment of CLL. METHODS: Screening a Wnt compound library with 75 Wnt modulators via ATP assay revealed Trichostatin A as an outstanding substance with strong viability decreasing effects on CLL cells and little effect on healthy peripheral blood mononuclear cells (PBMCs). Further survival analysis was performed via fluorescence-activated cell sorting analysis. RESULTS: A maximum effect was achieved after 48 h with a wide therapeutic window in contrast to PBMCs (CLL cells: 0.253 µM, PBMCs: 145.22 µM). Trichostatin A induced caspases and acted via a dual mechanism to reveal histone and non-histone targets. Histone targets were displayed in deacetylation inhibition at DNA level, and non-histone targeting was demonstrated by elevated levels of Dickkopf-related protein 1 mRNA. Primary cells of patients with critical mutations such as TP53 or those who had already undergone extensive previous treatment responded well to the treatment. Moreover, the approved histone deacetylase (HDAC) inhibitor suberoylanilidehydroxamic acid (SAHA) was not as effective as Trichostatin A (Trichostatin A: 0.253 µM, SAHA: 7.88 µM). Combining Trichostatin A with established CLL drugs fludarabine or bendamustine showed an additive effect in vitro. CONCLUSION: Taken together, Trichostatin A appears to act via a dual anti-HDAC/Wnt mechanism with a high selectivity and efficacy in CLL and therefore warrants further investigation.
Mraz M, Chen L, Rassenti LZ, et al. miR-150 influences B-cell receptor signaling in chronic lymphocytic leukemia by regulating expression of GAB1 and FOXP1. Blood. 2014; 124(1):84-95 [PubMed] Related Publications
We examined the microRNAs (miRNAs) expressed in chronic lymphocytic leukemia (CLL) and identified miR-150 as the most abundant, but with leukemia cell expression levels that varied among patients. CLL cells that expressed ζ-chain-associated protein of 70 kDa (ZAP-70) or that used unmutated immunoglobulin heavy chain variable (IGHV) genes, each had a median expression level of miR-150 that was significantly lower than that of ZAP-70-negative CLL cells or those that used mutated IGHV genes. In samples stratified for expression of miR-150, CLL cells with low-level miR-150 expressed relatively higher levels of forkhead box P1 (FOXP1) and GRB2-associated binding protein 1 (GAB1), genes with 3' untranslated regions having evolutionary-conserved binding sites for miR-150. High-level expression of miR-150 could repress expression of these genes, which encode proteins that enhance B-cell receptor signaling, a putative CLL-growth/survival signal. Also, high-level expression of miR-150 was a significant independent predictor of longer treatment-free survival or overall survival, whereas an inverse association was observed for high-level expression of GAB1 or FOXP1 for overall survival. This study demonstrates that expression of miR-150 can influence the relative expression of GAB1 and FOXP1 and the signaling potential of the B-cell receptor, thereby possibly accounting for the noted association of expression of miR-150 and disease outcome.
Chen X, Hu W, Xie B, et al. Downregulation of SCAI enhances glioma cell invasion and stem cell like phenotype by activating Wnt/β-catenin signaling. Biochem Biophys Res Commun. 2014; 448(2):206-11 [PubMed] Related Publications
SCAI (suppressor of cancer cell invasion), has been recently characterized as a novel tumor suppressor that inhibits the invasive migration of several human tumor cells. However, the expression pattern, biological role and molecular mechanism of SCAI in human glioma remain unknown. In this study, we found that levels of SCAI protein and mRNA expression were significantly down-regulated in glioma tissues and cell lines. Overexpression of SCAI inhibited, but silencing of SCAI robustly promoted the invasive and cancer stem cell-like phenotypes of glioma cells. Furthermore, we demonstrated that SCAI downregualtion activated the Wnt/β-catenin signaling, and blockade of the Wnt/β-catenin pathway abrogated the effects of SCAI downregulation on glioma cell aggressiveness. Taken together, our results provide the first demonstration of SCAI downregulation in glioma, and its downregulation contributes to increased glioma cell invasion and self-renewal by activating the Wnt/β-catenin pathway.
Zhang H, Yin Z, Ning K, et al. Prognostic value of microRNA-223/epithelial cell transforming sequence 2 signaling in patients with osteosarcoma. Hum Pathol. 2014; 45(7):1430-6 [PubMed] Related Publications
MicroRNA-223 (miR-223) has been demonstrated to be implicated in cell proliferation and cell cycle progression of osteosarcoma cell lines by regulating its target gene epithelial cell transforming sequence 2 (ECT2). However, the clinical significance of the deregulation of the miR-223/Ect2 axis in human osteosarcoma has not been fully elucidated. To address this problem, we firstly showed that the expression levels of miR-223 and Ect2 messenger RNA were, respectively, down-regulated and up-regulated in osteosarcoma tissues compared with those in noncancerous bone tissues significantly (both P < .001), according to the results of quantitative real-time reverse transcription-polymerase chain reaction. Notably, miR-223 down-regulation was negatively correlated with Ect2 messenger RNA up-regulation in osteosarcoma tissues (r = -0.68, P = .01). Then, the combined low miR-223 expression and high Ect2 expression (miR-223-low/Ect2-high) was significantly associated with high tumor grade (P = .01), poor response to chemotherapy (P = .01), positive metastasis (P < .001), and recurrence (P < .001) of osteosarcomas. Moreover, patients with miR-223-low/Ect2-high expression had the shortest overall survival (P < .001) and disease-free survival (P < .001) compared with patients in the other 3 groups (miR-223-low/Ect2-low, miR-223-high/Ect2-high, and miR-223-high/Ect2-low). Furthermore, the multivariate analysis identified miR-223/Ect2 expression and the status of metastasis as independent prognostic factors for overall survival and disease-free survival. In conclusion, our data offer convincing evidence that the deregulation of miR-223 and its target gene ECT2 may be associated with the aggressive tumor progression of human osteosarcoma. Of note, the combined miR-223 down-regulation and Ect2 up-regulation may be a possible marker of poor prognosis in this malignancy.
Yi T, Zhai B, Yu Y, et al. Quantitative phosphoproteomic analysis reveals system-wide signaling pathways downstream of SDF-1/CXCR4 in breast cancer stem cells. Proc Natl Acad Sci U S A. 2014; 111(21):E2182-90 [PubMed] Article available free on PMC after 27/11/2014 Related Publications
Breast cancer is the leading cause of cancer-related mortality in women worldwide, with an estimated 1.7 million new cases and 522,000 deaths around the world in 2012 alone. Cancer stem cells (CSCs) are essential for tumor reoccurrence and metastasis which is the major source of cancer lethality. G protein-coupled receptor chemokine (C-X-C motif) receptor 4 (CXCR4) is critical for tumor metastasis. However, stromal cell-derived factor 1 (SDF-1)/CXCR4-mediated signaling pathways in breast CSCs are largely unknown. Using isotope reductive dimethylation and large-scale MS-based quantitative phosphoproteome analysis, we examined protein phosphorylation induced by SDF-1/CXCR4 signaling in breast CSCs. We quantified more than 11,000 phosphorylation sites in 2,500 phosphoproteins. Of these phosphosites, 87% were statistically unchanged in abundance in response to SDF-1/CXCR4 stimulation. In contrast, 545 phosphosites in 266 phosphoproteins were significantly increased, whereas 113 phosphosites in 74 phosphoproteins were significantly decreased. SDF-1/CXCR4 increases phosphorylation in 60 cell migration- and invasion-related proteins, of them 43 (>70%) phosphoproteins are unrecognized. In addition, SDF-1/CXCR4 upregulates the phosphorylation of 44 previously uncharacterized kinases, 8 phosphatases, and 1 endogenous phosphatase inhibitor. Using computational approaches, we performed system-based analyses examining SDF-1/CXCR4-mediated phosphoproteome, including construction of kinase-substrate network and feedback regulation loops downstream of SDF-1/CXCR4 signaling in breast CSCs. We identified a previously unidentified SDF-1/CXCR4-PKA-MAP2K2-ERK signaling pathway and demonstrated the feedback regulation on MEK, ERK1/2, δ-catenin, and PPP1Cα in SDF-1/CXCR4 signaling in breast CSCs. This study gives a system-wide view of phosphorylation events downstream of SDF-1/CXCR4 signaling in breast CSCs, providing a resource for the study of CSC-targeted cancer therapy.
He S, Chen CH, Chernichenko N, et al. GFRα1 released by nerves enhances cancer cell perineural invasion through GDNF-RET signaling. Proc Natl Acad Sci U S A. 2014; 111(19):E2008-17 [PubMed] Article available free on PMC after 13/11/2014 Related Publications
The ability of cancer cells to invade along nerves is associated with aggressive disease and diminished patient survival rates. Perineural invasion (PNI) may be mediated by nerve secretion of glial cell line-derived neurotrophic factor (GDNF) attracting cancer cell migration through activation of cell surface Ret proto-oncogene (RET) receptors. GDNF family receptor (GFR)α1 acts as coreceptor with RET, with both required for response to GDNF. We demonstrate that GFRα1 released by nerves enhances PNI, even in the absence of cancer cell GFRα1 expression. Cancer cell migration toward GDNF, RET phosphorylation, and MAPK pathway activity are increased with exposure to soluble GFRα1 in a dose-dependent fashion. Dorsal root ganglia (DRG) release soluble GFRα1, which potentiates RET activation and cancer cell migration. In vitro DRG coculture assays of PNI show diminished PNI with DRG from GFRα1(+/-) mice compared with GFRα1(+/+) mice. An in vivo murine model of PNI demonstrates that cancer cells lacking GFRα1 maintain an ability to invade nerves and impair nerve function, whereas those lacking RET lose this ability. A tissue microarray of human pancreatic ductal adenocarcinomas demonstrates wide variance of cancer cell GFRα1 expression, suggesting an alternate source of GFRα1 in PNI. These findings collectively demonstrate that GFRα1 released by nerves enhances PNI through GDNF-RET signaling and that GFRα1 expression by cancer cells enhances but is not required for PNI. These results advance a mechanistic understanding of PNI and implicate the nerve itself as a key facilitator of this adverse cancer cell behavior.
Fotinos A, Nagarajan N, Martins AS, et al. Bone morphogenetic protein-focused strategies to induce cytotoxicity in lung cancer cells. Anticancer Res. 2014; 34(5):2095-104 [PubMed] Related Publications
BACKGROUND: High bone morphogenetic protein (BMP)-2 expression in lung carcinoma correlates with poor patient prognosis. The present study explored strategies to repress BMP signaling. MATERIALS AND METHODS: The cytotoxicity of BMP2-knockdown, dorsomorphin derivatives, and microRNAs was tested in transformed and non-transformed lung cells. Microarray analyses of 1,145 microRNAs in A549 lung adenocarcinoma cells and two other transformed lung cell types relative to BEAS-2B bronchial epithelial cells were performed. RESULTS: Reduced BMP2 synthesis inhibited A549 cell growth. The dorsomorphin derivative LDN-193189, but not DMH1 or DMH4, was strongly cytotoxic towards A549 cells, but not towards BEAS-2B cells. Microarray analysis revealed that 106 miRNAs were down-regulated and 69 miRNAs were up-regulated in the three transformed lines. Three down-regulated miRNAs, hsa-mir-34b, hsa-mir-34c-3p, and hsa-miR-486-3p, repressed a BMP2 reporter gene and were cytotoxic in A549 cells, but not towards BEAS-2B cells. CONCLUSION: The observed cytotoxicity suggests that reducing BMP signaling is a useful line of attack for therapy of lung cancer.
Xiong D, Liou Y, Shu J, et al. Down-regulating ribonuclease inhibitor enhances metastasis of bladder cancer cells through regulating epithelial-mesenchymal transition and ILK signaling pathway. Exp Mol Pathol. 2014; 96(3):411-21 [PubMed] Related Publications
Accumulating evidences implicate that ribonuclease inhibitor (RI) plays a suppressing role in cancer development. However, the mechanisms underlying antitumor of RI remain largely unknown. Epithelial-mesenchymal transition (EMT) is regarded as a key event in tumor progression. The reports have demonstrated that EMT was implicated in metastasis of bladder cancer. Therefore, we suppose that RI might involve regulating EMT of bladder cancer. Here bladder cancer T24 cells were transfected with pGensil-1-siRNA-RI vectors. HE staining, living cell observation, Phalloidine-FITC staining of microfilament, cell adhesion, scratch migration, and Matrigel invasion were examined respectively. RI expression and colocalization with ILK were detected using confocal microscope. Proteins associated with EMT were determined with Western blotting and immunohistochemistry in vivo and in vitro. Effects of RI expression on tumor growth, metastasis and EMT related proteins in BALB/C nude mouse and clinical human bladder cancer specimens were valued with histological, immunohistochemical and immunofluorescent examination respectively. We demonstrated that down-regulating RI increased cell proliferation, migration and invasion, changed cell morphology and adhesion, and rearranged cytoskeleton by inducing EMT and ILK signaling pathway in bladder cancer cells. In addition, we showed that down-regulating RI promoted tumorigenesis and metastasis of bladder cancer in vivo. Finally, we found that bladder cancer with invasive capability had higher Vimentin, Snail, Slug and Twist as well as lower E-cadherin and RI expression in clinical human specimens. Our results suggest that RI could play a novel role in inhibiting metastasis of bladder through regulating EMT and ILK signaling pathway.
Zhou S, Liu L, Li H, et al. Multipoint targeting of the PI3K/mTOR pathway in mesothelioma. Br J Cancer. 2014; 110(10):2479-88 [PubMed] Article available free on PMC after 13/05/2015 Related Publications
BACKGROUND: Mesothelioma is a notoriously chemotherapy-resistant neoplasm, as is evident in the dismal overall survival for patients with those of asbestos-associated disease. We previously demonstrated co-activation of multiple receptor tyrosine kinases (RTKs), including epidermal growth factor receptor (EGFR), MET, and AXL in mesothelioma cell lines, suggesting that these kinases could serve as novel therapeutic targets. Although clinical trials have not shown activity for EGFR inhibitors in mesothelioma, concurrent inhibition of various activated RTKs has pro-apoptotic and anti-proliferative effects in mesothelioma cell lines. Thus, we hypothesised that a coordinated network of multi-RTK activation contributes to mesothelioma tumorigenesis. METHODS: Activation of PI3K/AKT/mTOR, Raf/MAPK, and co-activation of RTKs were evaluated in mesotheliomas. Effects of RTK and downstream inhibitors/shRNAs were assessed by measuring mesothelioma cell viability/growth, apoptosis, activation of signalling intermediates, expression of cell-cycle checkpoints, and cell-cycle alterations. RESULTS: We demonstrate activation of the PI3K/AKT/p70S6K and RAF/MEK/MAPK pathways in mesothelioma, but not in non-neoplastic mesothelial cells. The AKT activation, but not MAPK activation, was dependent on coordinated activation of RTKs EGFR, MET, and AXL. In addition, PI3K/AKT/mTOR pathway inhibition recapitulated the anti-proliferative effects of concurrent inhibition of EGFR, MET, and AXL. Dual targeting of PI3K/mTOR by BEZ235 or a combination of RAD001 and AKT knockdown had a greater effect on mesothelioma proliferation and viability than inhibition of individual activated RTKs or downstream signalling intermediates. Inhibition of PI3K/AKT was also associated with MDM2-p53 cell-cycle regulation. CONCLUSIONS: These findings show that PI3K/AKT/mTOR is a crucial survival pathway downstream of multiple activated RTKs in mesothelioma, underscoring that PI3K/mTOR is a compelling target for therapeutic intervention.