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Signal Transduction

"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)

An overview of major signal transduction pathways
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)

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Web Resources: Signal Transduction and Cancer
Latest Research Publications

Web Resources: Signal Transduction and Cancer (3 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Xue G, Zippelius A, Wicki A, et al.
Integrated Akt/PKB signaling in immunomodulation and its potential role in cancer immunotherapy.
J Natl Cancer Inst. 2015; 107(7) [PubMed] Related Publications
T cell development and maturation involve a variety of defined and coordinated developmental stages under the control of a variety of signaling networks. They function as the major mediator in cell-based immunity that defends against pathogen infections and executes immune surveillance against tumor cells. Protein kinase B (PKB, also called Akt) is central to multiple signaling pathways and transduces extracellular signals to dictate cellular responses towards proliferation, migration, anti-apoptosis, and maintenance of metabolic homeostasis. Although the prosurvival function of PKB was thought to be responsible for most of the functions regulated by PKB, emerging evidence has started to dissect its role in immunomodulation. More importantly, hyperactivation of PKB in cancer stroma frequently occurs in patients treated clinically with targeted cancer therapies, where it acts as a key mediator involved in the trapping of host immune cells in the vicinity of tumors, which supports cancer cell invasion and the escape of cancer cells from host immune surveillance. Encouragingly, recent studies have shown that inhibition of PKB improves the recognition of cancer cells by the host immune system, indicating a potential clinical strategy to rekindle the suppressed host immune response through the specific targeting of PKB. In this review, we explore how PKB signaling contributes to T cell development and cellular immune responses and discuss the mechanistic roles that PKB plays in the creation of immunosuppressive conditions and the escaping of immune recognition in the microenvironment of cancer.

Desideri E, Cavallo AL, Baccarini M
Alike but Different: RAF Paralogs and Their Signaling Outputs.
Cell. 2015; 161(5):967-70 [PubMed] Related Publications
RAF links RAS, one of the most potent human oncogenes, to its effector ERK and to proliferation. This role is evolutionarily conserved, but while simpler multicellular organisms express one RAF, mammals have three. This Minireview highlights common and divergent features of RAF paralogs, their signaling outputs, and roles in tumorigenesis.

Aguayo RS, Rafel M, Santacana M, et al.
Erk1/2 activation in stromal fibroblasts from sporadic basal cell carcinomas.
Dermatol Surg. 2015; 41(6):677-84 [PubMed] Related Publications
BACKGROUND: Constitutive activation of the Erk pathway can lead to oncogenic transformation. However, the Erk pathway is not activated in human basal cell carcinomas (BCCs); although in animal models, this seems to be important.
OBJECTIVE: To help understand the role of Erk activity in BCC formation.
MATERIALS AND METHODS: The authors assayed the specific levels of phosphorylated Erk by immunohistochemistry in BCCs and normal skin biopsies. They have also analyzed Erk activation by immunoblot in fibroblasts isolated from BCC.
RESULTS: By immunohistochemical analysis, the authors have observed that 10 of BCCs (56%) did not show phosphor-Erk staining in tumor masses and 7 (40%) showed a gradient staining exhibiting phospho-Erk only in the epidermal side of tumor masses. Remarkably, 15 BCC samples (83%) showed phospho-Erk accumulation in stroma. Six of the 9 independent cultures of dermal fibroblasts isolated from BCC maintained Erk activation "in vitro."
CONCLUSION: The authors propose that there is a specific cell-type regulation of Erk activity in BCC, and this feature may be relevant during BCC formation. Stroma region from BCCs showed Erk activation and reduced proliferation. Conversely, Erk activation is barely detectable in proliferative BCCs.

Challagundla KB, Wise PM, Neviani P, et al.
Exosome-mediated transfer of microRNAs within the tumor microenvironment and neuroblastoma resistance to chemotherapy.
J Natl Cancer Inst. 2015; 107(7) [PubMed] Related Publications
BACKGROUND: How exosomic microRNAs (miRNAs) contribute to the development of drug resistance in the context of the tumor microenvironment has not been previously described in neuroblastoma (NBL).
METHODS: Coculture experiments were performed to assess exosomic transfer of miR-21 from NBL cells to human monocytes and miR-155 from human monocytes to NBL cells. Luciferase reporter assays were performed to assess miR-155 targeting of TERF1 in NBL cells. Tumor growth was measured in NBL xenografts treated with Cisplatin and peritumoral exosomic miR-155 (n = 6 mice per group) CD163, miR-155, and TERF1 levels were assessed in 20 NBL primary tissues by Human Exon Arrays and quantitative real-time polymerase chain reaction. Student's t test was used to evaluate the differences between treatment groups. All statistical tests were two-sided.
RESULTS: miR-21 mean fold change (f.c.) was 12.08±0.30 (P < .001) in human monocytes treated with NBL derived exosomes for 48 hours, and miR-155 mean f.c. was 4.51±0.25 (P < .001) in NBL cells cocultured with human monocytes for 48 hours. TERF1 mean luciferase activity in miR-155 transfected NBL cells normalized to scrambled was 0.36 ± 0.05 (P <.001). Mean tumor volumes in Dotap-miR-155 compared with Dotap-scrambled were 322.80±120mm(3) and 76.00±39.3mm(3), P = .002 at day 24, respectively. Patients with high CD163 infiltrating NBLs had statistically significantly higher intratumoral levels of miR-155 (P = .04) and lower levels of TERF1 mRNA (P = .02).
CONCLUSIONS: These data indicate a unique role of exosomic miR-21 and miR-155 in the cross-talk between NBL cells and human monocytes in the resistance to chemotherapy, through a novel exosomic miR-21/TLR8-NF-кB/exosomic miR-155/TERF1 signaling pathway.

Spranger S, Bao R, Gajewski TF
Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity.
Nature. 2015; 523(7559):231-5 [PubMed] Related Publications
Melanoma treatment is being revolutionized by the development of effective immunotherapeutic approaches. These strategies include blockade of immune-inhibitory receptors on activated T cells; for example, using monoclonal antibodies against CTLA-4, PD-1, and PD-L1 (refs 3-5). However, only a subset of patients responds to these treatments, and data suggest that therapeutic benefit is preferentially achieved in patients with a pre-existing T-cell response against their tumour, as evidenced by a baseline CD8(+) T-cell infiltration within the tumour microenvironment. Understanding the molecular mechanisms that underlie the presence or absence of a spontaneous anti-tumour T-cell response in subsets of cases, therefore, should enable the development of therapeutic solutions for patients lacking a T-cell infiltrate. Here we identify a melanoma-cell-intrinsic oncogenic pathway that contributes to a lack of T-cell infiltration in melanoma. Molecular analysis of human metastatic melanoma samples revealed a correlation between activation of the WNT/β-catenin signalling pathway and absence of a T-cell gene expression signature. Using autochthonous mouse melanoma models we identified the mechanism by which tumour-intrinsic active β-catenin signalling results in T-cell exclusion and resistance to anti-PD-L1/anti-CTLA-4 monoclonal antibody therapy. Specific oncogenic signals, therefore, can mediate cancer immune evasion and resistance to immunotherapies, pointing to new candidate targets for immune potentiation.

Tu HC, Schwitalla S, Qian Z, et al.
LIN28 cooperates with WNT signaling to drive invasive intestinal and colorectal adenocarcinoma in mice and humans.
Genes Dev. 2015; 29(10):1074-86 [PubMed] Article available free on PMC after 15/11/2015 Related Publications
Colorectal cancer (CRC) remains a major contributor to cancer-related mortality. LIN28A and LIN28B are highly related RNA-binding protein paralogs that regulate biogenesis of let-7 microRNAs and influence development, metabolism, tissue regeneration, and oncogenesis. Here we demonstrate that overexpression of either LIN28 paralog cooperates with the Wnt pathway to promote invasive intestinal adenocarcinoma in murine models. When LIN28 alone is induced genetically, half of the resulting tumors harbor Ctnnb1 (β-catenin) mutation. When overexpressed in Apc(Min/+) mice, LIN28 accelerates tumor formation and enhances proliferation and invasiveness. In conditional genetic models, enforced expression of a LIN28-resistant form of the let-7 microRNA reduces LIN28-induced tumor burden, while silencing of LIN28 expression reduces tumor volume and increases tumor differentiation, indicating that LIN28 contributes to tumor maintenance. We detected aberrant expression of LIN28A and/or LIN28B in 38% of a large series of human CRC samples (n = 595), where LIN28 expression levels were associated with invasive tumor growth. Our late-stage CRC murine models and analysis of primary human tumors demonstrate prominent roles for both LIN28 paralogs in promoting CRC growth and progression and implicate the LIN28/let-7 pathway as a therapeutic target.

Zhang L, Wang H, Ding K, Xu J
FTY720 induces autophagy-related apoptosis and necroptosis in human glioblastoma cells.
Toxicol Lett. 2015; 236(1):43-59 [PubMed] Related Publications
FTY720 is a potent immunosuppressant which has preclinical antitumor efficacy in various cancer models. However, its role in glioblastoma remains unclear. In the present study, we found that FTY720 induced extrinsic apoptosis, necroptosis and autophagy in human glioblastoma cells. Inhibition of autophagy by either RNA interference or chemical inhibitors attenuated FTY720-induced apoptosis and necrosis. Furthermore, autophagy, apoptosis and necrosis induction were dependent on reactive oxygen species-c-Jun N-terminal kinase-protein 53 (ROS-JNK-p53) loop mediated phosphatidylinositide 3-kinases/protein kinase B/mammalian target of rapamycin/p70S6 kinase (PI3K/AKT/mTOR/p70S6K) pathway. In addition, receptor-interacting protein 1 and 3 (RIP1 and RIP3) served as an upstream of ROS-JNK-p53 loop. However, the phosphorylation form of FTY720 induced autophagy but not apoptosis and necroptosis. Finally, the in vitro results were validated in vivo in xenograft mouse of glioblastoma cells. In conclusion, the current study provided novel insights into understanding the mechanisms and functions of FTY720-induced apoptosis, necroptosis and autophagy in human glioblastoma cells.

Wang F, Ruan XJ, Zhang HY
BDE-99 (2,2',4,4',5-pentabromodiphenyl ether) triggers epithelial-mesenchymal transition in colorectal cancer cells via PI3K/Akt/Snail signaling pathway.
Tumori. 2015 Mar-Apr; 101(2):238-45 [PubMed] Related Publications
PURPOSE: The gut is in direct contact with BDE-99 (2,2',4,4',5-pentabromodiphenyl ether), one of the most abundant PBDE congeners in the environment and in human tissues. The objective of the present study was to investigate the effects of BDE-99 on colorectal cancer (CRC) cells.
METHODS: The effects of BDE-99 on cell proliferation were measured by CCK-8 assay in the CRC cell line HCT-116. Wound healing and transwell migration/invasion assays were used to test the migration and invasion of CRC cells. Factors related to epithelial-to-mesenchymal transition (EMT) were measured by real-time PCR and Western blot analysis for mRNA and protein levels, respectively.
RESULTS: BDE-99 was found to increase migration and invasion and trigger EMT in HCT-116 cells; EMT was characterized by cells acquiring mesenchymal spindle-like morphology and by increased expression of N-cadherin with a concomitant decrease in E-cadherin. BDE-99 treatment also increased the protein and mRNA levels of the transcription factor Snail, but not Slug, Twist, and ZEB1. Knockdown of Snail by siRNA significantly attenuated BDE-99-induced EMT in HCT-116 cells, suggesting that Snail plays a crucial role in BDE-99-induced EMT. The PI3K/Akt inhibitor LY294002 completely blocked BDE-99-induced Snail and invasion of HCT-116 cells.
CONCLUSIONS: Our results revealed that BDE-99 can trigger the EMT of colon cancer cells via the PI3K/AKT/Snail signaling pathway. This study provides new insight into the tumorigenesis and metastasis of CRC stimulated by BDE-99 and possibly other PBDE congeners.

Wei SC, Fattet L, Tsai JH, et al.
Matrix stiffness drives epithelial-mesenchymal transition and tumour metastasis through a TWIST1-G3BP2 mechanotransduction pathway.
Nat Cell Biol. 2015; 17(5):678-88 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
Matrix stiffness potently regulates cellular behaviour in various biological contexts. In breast tumours, the presence of dense clusters of collagen fibrils indicates increased matrix stiffness and correlates with poor survival. It is unclear how mechanical inputs are transduced into transcriptional outputs to drive tumour progression. Here we report that TWIST1 is an essential mechanomediator that promotes epithelial-mesenchymal transition (EMT) in response to increasing matrix stiffness. High matrix stiffness promotes nuclear translocation of TWIST1 by releasing TWIST1 from its cytoplasmic binding partner G3BP2. Loss of G3BP2 leads to constitutive TWIST1 nuclear localization and synergizes with increasing matrix stiffness to induce EMT and promote tumour invasion and metastasis. In human breast tumours, collagen fibre alignment, a marker of increasing matrix stiffness, and reduced expression of G3BP2 together predict poor survival. Our findings reveal a TWIST1-G3BP2 mechanotransduction pathway that responds to biomechanical signals from the tumour microenvironment to drive EMT, invasion and metastasis.

Menendez JA, Schroeder B, Peirce SK, et al.
Blockade of a key region in the extracellular domain inhibits HER2 dimerization and signaling.
J Natl Cancer Inst. 2015; 107(6):djv090 [PubMed] Related Publications
BACKGROUND: Several treatment strategies target the human epidermal growth factor receptor 2 (HER2) in breast carcinomas, including monoclonal antibodies directed against HER2's extracellular domain (ECD) and small molecule inhibitors of its tyrosine kinase activity. Yet, novel therapies are needed that prevent HER2 dimerization with other HER family members, because current treatments are only partially effective.
METHODS: To test the hypothesis that HER2 activation requires a protein sequence in the HER2-ECD that mediates HER2 homo- and heterodimerization, we introduced a series of deletion mutations in the third subdomain of HER2-ECD. These deletion mutants were retrovirally expressed in breast cancer (BC) cells that naturally overexpress HER2 and in noncancerous, HER2-negative breast epithelial cells. One-factor analysis of variance or Student's t test were used to analyze differences. All statistical tests were two-sided.
RESULTS: The smallest deletion in the ECD domain of HER2, which removed only 16 amino acids (HER2-ECDΔ451-466), completely disrupted the oncogenic potential of HER2. In contrast to wild-type HER2, the mutant-inhibited anchorage-independent growth (mean number of colonies: mutant, 70, 95% confidence interval [CI] = 55 to 85; wild-type, 400, 95% CI = 320 to 480, P < .001) increased sensitivity to paclitaxel treatment in both transformed and nontransformed cells. Overexpression of HER2Δ451-466 efficiently inhibited activation of HER1, HER2, and HER3 in all cell lines tested.
CONCLUSIONS: These findings reveal that an essential "activating" sequence exists in the extracellular domain of HER2. Disruption of this sequence disables the HER2 dimerization loop, blocks subsequent activation of HER2-driven oncogenic signaling, and generates a dominant-negative form of HER2. Reagents specifically against this molecular activation switch may represent a novel targeted approach for the management of HER2-overexpressing carcinomas.

De Miguel D, Gallego-Lleyda A, Anel A, Martinez-Lostao L
Liposome-bound TRAIL induces superior DR5 clustering and enhanced DISC recruitment in histiocytic lymphoma U937 cells.
Leuk Res. 2015; 39(6):657-66 [PubMed] Related Publications
Human Apo2-Ligand/TRAIL is a promising antitumor agent. Our group demonstrated that TRAIL was physiologically released to the extracellular medium inserted in lipid vesicles, known as exosomes. Recently we demonstrated that artificial lipid nanoparticles coated with bioactive TRAIL (LUV-TRAIL), which resemble the natural exosomes, greatly improved TRAIL activity compared with the soluble form of this death ligand and were able to induce apoptosis in hematological malignancies. In this study we have deepened the underlying mechanism of action of LUV-TRAIL in hematologic cells. Using histiocytic lymphoma U937 cells, we demonstrated that TRAIL signaling almost exclusively depends on DR5 despite these cells expressing high amounts of DR4, and proved that LUV-TRAIL's higher pro-apoptotic effect relies on its superior ability to induce DR5 clustering on cell surface, therefore enhancing DISC recruitment and triggering caspase activation more efficiently than the soluble form of TRAIL.

Zhang MZ, Ferrigno O, Wang Z, et al.
TGIF governs a feed-forward network that empowers Wnt signaling to drive mammary tumorigenesis.
Cancer Cell. 2015; 27(4):547-60 [PubMed] Article available free on PMC after 13/04/2016 Related Publications
Many types of human cancers having hyperactivated Wnt signaling display no causative alterations in known effectors of this pathway. Here, we report a function of TGIF in Wnt signaling. TGIF associates with and diverts Axin1 and Axin2 from the β-catenin destruction complex, therefore allowing β-catenin accrual. Intriguingly, activation of Wnt signaling induces the expression of TGIF, which unveils a feed-forward loop that ensures effective integration of Wnt signaling. In triple-negative breast cancers (TNBC), elevated levels of TGIF correlate with high Wnt signaling and poor survival of patients. Moreover, genetic experiments revealed that Tgif1 ablation impeded mammary tumor development in MMTV-Wnt1 mice, further underscoring a requirement of TGIF for oncogenic Wnt signaling.

Andrikopoulou M, Salakos N, Deligeoroglou E, et al.
The role of mTOR signaling pathway in premalignant and malignant cervical lesions.
Eur J Gynaecol Oncol. 2015; 36(1):36-43 [PubMed] Related Publications
PURPOSE OF THE STUDY: Aberrant activation of the Akt/mTOR/pS6 signaling pathway has been identified in various types of cancer and is under investigation in cervical cancer. The purpose of this study was to assess the expression of the phosphorylated/activated forms of Akt (upstream molecule), 4E-BP1 and pS6 (downstream molecules) in biopsy samples of cervical low grade squamous intraepithelial lesions (LSIL), high grade squamous intraepithelial lesions (HSIL), and squamous cell carcinoma (Ca) compared to normal cervical epithelium.
MATERIAL AND METHODS: The study included 38 cases diagnosed as LSIL, 31 cases as HSIL, 29 cases as Ca, and eight control cases from normal cervix. Immunohistochemistry was used to assess the expression of pAkt, p4E-BP1 and pS6.
RESULTS: Statistical analysis revealed significant differences between HSIL and Ca groups compared to controls regarding intensity, positivity, and total scores for all three molecules (p < 0.001). A trend for higher expression with increasing grade of dysplasia was demonstrated.
CONCLUSION: These results strongly support the view that the mTOR signaling pathway is involved in cervical carcinogenesis.

Yen HR, Liu CJ, Yeh CC
Naringenin suppresses TPA-induced tumor invasion by suppressing multiple signal transduction pathways in human hepatocellular carcinoma cells.
Chem Biol Interact. 2015; 235:1-9 [PubMed] Related Publications
Naringenin, a common dietary flavonoid abundantly present in fruits and vegetables, is believed to possess strong anti-proliferative properties and the ability to induce apoptosis in hepatoma cell lines. However, there are no reports describing its effects on the invasion and metastasis of hepatoma cell lines, and the detailed molecular mechanisms of its effects are still unclear. In this study, we investigated the mechanisms underlying naringenin-mediated inhibition of 12-O-Tetradecanoylphorbol-13-acetate (TPA)-induced cell invasion and inhibition of secreted and cytosolic MMP-9 production in human hepatoma cells (HepG2, Huh-7, and HA22T) and murine embryonic liver cells (BNL CL2). Naringenin suppressed MMP-9 transcription by inhibiting activator protein (AP)-1 and nuclear factor-κB (NF-κB) activity. It suppressed TPA-induced AP-1 activity through inhibiting the phosphorylation of the extracellular signal-related kinase (ERK) and c-Jun N-terminal kinase (JNK) signaling pathways, and it suppressed TPA-induced inhibition of NF-κB nuclear translocation through IκB. Additionally, it suppressed TPA-induced activation of ERK/phosphatidylinositol 3-kinase/Akt upstream of NF-κB and AP-1. These data suggest that naringenin suppresses the invasiveness and metastatic potential of hepatocellular carcinoma (HCC) by inhibiting multiple signal transduction pathways.

Bist P, Phua QH, Shu S, et al.
Annexin-A1 controls an ERK-RhoA-NFκB activation loop in breast cancer cells.
Biochem Biophys Res Commun. 2015; 461(1):47-53 [PubMed] Related Publications
Wound healing is critical for normal development and pathological processes including cancer cell metastasis. MAPK, Rho-GTPases and NFκB are important regulators of wound healing, but mechanisms for their integration are incompletely understood. Annexin-A1 (ANXA1) is upregulated in invasive breast cancer cells resulting in constitutive activation of NFκB. We show here that silencing ANXA1 increases the formation of stress fibers and focal adhesions, which may inhibit wound healing. ANXA1 regulated wound healing is dependent on the activation of ERK1/2. ANXA1 increases the activation of RhoA, which is dependent on ERK activation. Furthermore, active RhoA is important in NF-κB activation, where constitutively active RhoA potentiates NFκB activation, while dominant negative RhoA inhibits NFκB activation in response to CXCL12 stimulation and active MEKK plasmids. These findings establish a central role for ANXA1 in the cell migration through the activation of NFκB, ERK1/2 and RhoA.

Wu H, Gao L, Li F, et al.
Identifying overlapping mutated driver pathways by constructing gene networks in cancer.
BMC Bioinformatics. 2015; 16 Suppl 5:S3 [PubMed] Article available free on PMC after 13/04/2016 Related Publications
BACKGROUND: Large-scale cancer genomic projects are providing lots of data on genomic, epigenomic and gene expression aberrations in many cancer types. One key challenge is to detect functional driver pathways and to filter out nonfunctional passenger genes in cancer genomics. Vandin et al. introduced the Maximum Weight Sub-matrix Problem to find driver pathways and showed that it is an NP-hard problem.
METHODS: To find a better solution and solve the problem more efficiently, we present a network-based method (NBM) to detect overlapping driver pathways automatically. This algorithm can directly find driver pathways or gene sets de novo from somatic mutation data utilizing two combinatorial properties, high coverage and high exclusivity, without any prior information. We firstly construct gene networks based on the approximate exclusivity between each pair of genes using somatic mutation data from many cancer patients. Secondly, we present a new greedy strategy to add or remove genes for obtaining overlapping gene sets with driver mutations according to the properties of high exclusivity and high coverage.
RESULTS: To assess the efficiency of the proposed NBM, we apply the method on simulated data and compare results obtained from the NBM, RME, Dendrix and Multi-Dendrix. NBM obtains optimal results in less than nine seconds on a conventional computer and the time complexity is much less than the three other methods. To further verify the performance of NBM, we apply the method to analyze somatic mutation data from five real biological data sets such as the mutation profiles of 90 glioblastoma tumor samples and 163 lung carcinoma samples. NBM detects groups of genes which overlap with known pathways, including P53, RB and RTK/RAS/PI(3)K signaling pathways. New gene sets with p-value less than 1e-3 are found from the somatic mutation data.
CONCLUSIONS: NBM can detect more biologically relevant gene sets. Results show that NBM outperforms other algorithms for detecting driver pathways or gene sets. Further research will be conducted with the use of novel machine learning techniques.

Sudarikova AV, Tsaplina OA, Chubinskiy-Nadezhdin VI, et al.
Amiloride-insensitive sodium channels are directly regulated by actin cytoskeleton dynamics in human lymphoma cells.
Biochem Biophys Res Commun. 2015; 461(1):54-8 [PubMed] Related Publications
Sodium influx mediated by ion channels of plasma membrane underlies fundamental physiological processes in cells of blood origin. However, little is known about the single channel activity and regulatory mechanisms of sodium-specific channels in native cells. In the present work, we used different modes of patch clamp technique to examine ion channels involved in Na-transporting pathway in U937 human lymphoma cells. The activity of native non-voltage-gated sodium (NVGS) channels with unitary conductance of 10 pS was revealed in cell-attached, inside-out and whole-cell configurations. NVGS channel activity is directly controlled by submembranous actin cytoskeleton. Specifically, an activation of sodium channels in U937 cells in response to microfilament disassembly was demonstrated on single-channel and integral current level. Inside-out experiments showed that filament assembly on cytoplasmic membrane surface caused fast inactivation of the channels. Biophysical characteristics of NVGS channels in U937 cells were similar to that of epithelial sodium channels (ENaCs). However, we found that amiloride, a known inhibitor of DEG/ENaC, did not block NVGS channels in U937 cells. Whole-cell current measurements revealed no amiloride-sensitive component of membrane current. Our data show that cortical actin structures represent the main factor that controls the activity of amiloride-insensitive ENaC-like channels in human lymphoma cells.

Pérez-Gómez E, Andradas C, Blasco-Benito S, et al.
Role of cannabinoid receptor CB2 in HER2 pro-oncogenic signaling in breast cancer.
J Natl Cancer Inst. 2015; 107(6):djv077 [PubMed] Related Publications
BACKGROUND: Pharmacological activation of cannabinoid receptors elicits antitumoral responses in different cancer models. However, the biological role of these receptors in tumor physio-pathology is still unknown.
METHODS: We analyzed CB2 cannabinoid receptor protein expression in two series of 166 and 483 breast tumor samples operated in the University Hospitals of Kiel, Tübingen, and Freiburg between 1997 and 2010 and CB2 mRNA expression in previously published DNA microarray datasets. The role of CB2 in oncogenesis was studied by generating a mouse line that expresses the human V-Erb-B2 Avian Erythroblastic Leukemia Viral Oncogene Homolog 2 (HER2) rat ortholog (neu) and lacks CB2 and by a variety of biochemical and cell biology approaches in human breast cancer cells in culture and in vivo, upon modulation of CB2 expression by si/shRNAs and overexpression plasmids. CB2-HER2 molecular interaction was studied by colocalization, coimmunoprecipitation, and proximity ligation assays. Statistical tests were two-sided.
RESULTS: We show an association between elevated CB2 expression in HER2+ breast tumors and poor patient prognosis (decreased overall survival, hazard ratio [HR] = 0.29, 95% confidence interval [CI] = 0.09 to 0.71, P = .009) and higher probability to suffer local recurrence (HR = 0.09, 95% CI = 0.049 to 0.54, P = .003) and to develop distant metastases (HR = 0.33, 95% CI = 0.13 to 0.75, P = .009). We also demonstrate that genetic inactivation of CB2 impairs tumor generation and progression in MMTV-neu mice. Moreover, we show that HER2 upregulates CB2 expression by activating the transcription factor ELK1 via the ERK cascade and that an increased CB2 expression activates the HER2 pro-oncogenic signaling at the level of the tyrosine kinase c-SRC. Finally, we show HER2 and CB2 form heteromers in cancer cells.
CONCLUSIONS: Our findings reveal an unprecedented role of CB2 as a pivotal regulator of HER2 pro-oncogenic signaling in breast cancer, and they suggest that CB2 may be a biomarker with prognostic value in these tumors.

Furnari FB, Cloughesy TF, Cavenee WK, Mischel PS
Heterogeneity of epidermal growth factor receptor signalling networks in glioblastoma.
Nat Rev Cancer. 2015; 15(5):302-10 [PubMed] Related Publications
As tumours evolve, the daughter cells of the initiating cell often become molecularly heterogeneous and develop different functional properties and therapeutic vulnerabilities. In glioblastoma (GBM), a lethal form of brain cancer, the heterogeneous expression of the epidermal growth factor receptor (EGFR) poses a substantial challenge for the effective use of EGFR-targeted therapies. Understanding the mechanisms that cause EGFR heterogeneity in GBM should provide better insights into how they, and possibly other amplified receptor tyrosine kinases, affect cellular signalling, metabolism and drug resistance.

Buchtova M, Chaloupkova R, Zakrzewska M, et al.
Instability restricts signaling of multiple fibroblast growth factors.
Cell Mol Life Sci. 2015; 72(12):2445-59 [PubMed] Related Publications
Fibroblast growth factors (FGFs) deliver extracellular signals that govern many developmental and regenerative processes, but the mechanisms regulating FGF signaling remain incompletely understood. Here, we explored the relationship between intrinsic stability of FGF proteins and their biological activity for all 18 members of the FGF family. We report that FGF1, FGF3, FGF4, FGF6, FGF8, FGF9, FGF10, FGF16, FGF17, FGF18, FGF20, and FGF22 exist as unstable proteins, which are rapidly degraded in cell cultivation media. Biological activity of FGF1, FGF3, FGF4, FGF6, FGF8, FGF10, FGF16, FGF17, and FGF20 is limited by their instability, manifesting as failure to activate FGF receptor signal transduction over long periods of time, and influence specific cell behavior in vitro and in vivo. Stabilization via exogenous heparin binding, introduction of stabilizing mutations or lowering the cell cultivation temperature rescues signaling of unstable FGFs. Thus, the intrinsic ligand instability is an important elementary level of regulation in the FGF signaling system.

Schmid CA, Robinson MD, Scheifinger NA, et al.
DUSP4 deficiency caused by promoter hypermethylation drives JNK signaling and tumor cell survival in diffuse large B cell lymphoma.
J Exp Med. 2015; 212(5):775-92 [PubMed] Article available free on PMC after 04/11/2015 Related Publications
The epigenetic dysregulation of tumor suppressor genes is an important driver of human carcinogenesis. We have combined genome-wide DNA methylation analyses and gene expression profiling after pharmacological DNA demethylation with functional screening to identify novel tumor suppressors in diffuse large B cell lymphoma (DLBCL). We find that a CpG island in the promoter of the dual-specificity phosphatase DUSP4 is aberrantly methylated in nodal and extranodal DLBCL, irrespective of ABC or GCB subtype, resulting in loss of DUSP4 expression in 75% of >200 examined cases. The DUSP4 genomic locus is further deleted in up to 13% of aggressive B cell lymphomas, and the lack of DUSP4 is a negative prognostic factor in three independent cohorts of DLBCL patients. Ectopic expression of wild-type DUSP4, but not of a phosphatase-deficient mutant, dephosphorylates c-JUN N-terminal kinase (JNK) and induces apoptosis in DLBCL cells. Pharmacological or dominant-negative JNK inhibition restricts DLBCL survival in vitro and in vivo and synergizes strongly with the Bruton's tyrosine kinase inhibitor ibrutinib. Our results indicate that DLBCL cells depend on JNK signaling for survival. This finding provides a mechanistic basis for the clinical development of JNK inhibitors in DLBCL, ideally in synthetic lethal combinations with inhibitors of chronic active B cell receptor signaling.

Zhang L, Zhou Y, Cheng C, et al.
Genomic analyses reveal mutational signatures and frequently altered genes in esophageal squamous cell carcinoma.
Am J Hum Genet. 2015; 96(4):597-611 [PubMed] Article available free on PMC after 04/11/2015 Related Publications
Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers worldwide and the fourth most lethal cancer in China. However, although genomic studies have identified some mutations associated with ESCC, we know little of the mutational processes responsible. To identify genome-wide mutational signatures, we performed either whole-genome sequencing (WGS) or whole-exome sequencing (WES) on 104 ESCC individuals and combined our data with those of 88 previously reported samples. An APOBEC-mediated mutational signature in 47% of 192 tumors suggests that APOBEC-catalyzed deamination provides a source of DNA damage in ESCC. Moreover, PIK3CA hotspot mutations (c.1624G>A [p.Glu542Lys] and c.1633G>A [p.Glu545Lys]) were enriched in APOBEC-signature tumors, and no smoking-associated signature was observed in ESCC. In the samples analyzed by WGS, we identified focal (<100 kb) amplifications of CBX4 and CBX8. In our combined cohort, we identified frequent inactivating mutations in AJUBA, ZNF750, and PTCH1 and the chromatin-remodeling genes CREBBP and BAP1, in addition to known mutations. Functional analyses suggest roles for several genes (CBX4, CBX8, AJUBA, and ZNF750) in ESCC. Notably, high activity of hedgehog signaling and the PI3K pathway in approximately 60% of 104 ESCC tumors indicates that therapies targeting these pathways might be particularly promising strategies for ESCC. Collectively, our data provide comprehensive insights into the mutational signatures of ESCC and identify markers for early diagnosis and potential therapeutic targets.

Sharma P, Allison JP
The future of immune checkpoint therapy.
Science. 2015; 348(6230):56-61 [PubMed] Related Publications
Immune checkpoint therapy, which targets regulatory pathways in T cells to enhance antitumor immune responses, has led to important clinical advances and provided a new weapon against cancer. This therapy has elicited durable clinical responses and, in a fraction of patients, long-term remissions where patients exhibit no clinical signs of cancer for many years. The way forward for this class of novel agents lies in our ability to understand human immune responses in the tumor microenvironment. This will provide valuable information regarding the dynamic nature of the immune response and regulation of additional pathways that will need to be targeted through combination therapies to provide survival benefit for greater numbers of patients.

Yeh YY, Ozer HG, Lehman AM, et al.
Characterization of CLL exosomes reveals a distinct microRNA signature and enhanced secretion by activation of BCR signaling.
Blood. 2015; 125(21):3297-305 [PubMed] Article available free on PMC after 21/05/2016 Related Publications
Multiple studies show that chronic lymphocytic leukemia (CLL) cells are heavily dependent on their microenvironment for survival. Communication between CLL cells and the microenvironment is mediated through direct cell contact, soluble factors, and extracellular vesicles. Exosomes are small particles enclosed with lipids, proteins, and small RNAs that can convey biological materials to surrounding cells. Our data herein demonstrate that CLL cells release significant amounts of exosomes in plasma that exhibit abundant CD37, CD9, and CD63 expression. Our work also pinpoints the regulation of B-cell receptor (BCR) signaling in the release of CLL exosomes: BCR activation by α-immunoglobulin (Ig)M induces exosome secretion, whereas BCR inactivation via ibrutinib impedes α-IgM-stimulated exosome release. Moreover, analysis of serial plasma samples collected from CLL patients on an ibrutinib clinical trial revealed that exosome plasma concentration was significantly decreased following ibrutinib therapy. Furthermore, microRNA (miR) profiling of plasma-derived exosomes identified a distinct exosome microRNA signature, including miR-29 family, miR-150, miR-155, and miR-223 that have been associated with CLL disease. Interestingly, expression of exosome miR-150 and miR-155 increases with BCR activation. In all, this study successfully characterized CLL exosomes, demonstrated the control of BCR signaling in the release of CLL exosomes, and uncovered a disease-relevant exosome microRNA profile.

Lin X, Fang Q, Chen S, et al.
Heme oxygenase-1 suppresses the apoptosis of acute myeloid leukemia cells via the JNK/c-JUN signaling pathway.
Leuk Res. 2015; 39(5):544-52 [PubMed] Related Publications
There are few studies on the correlation between heme oxygenase-1 (HO-1) and acute myeloid leukemia (AML). We found that HO-1 was aberrantly overexpressed in the majority of AML patients, especially in patients with acute monocytic leukemia (M5) and leukocytosis, and inhibited the apoptosis of HL-60 and U937 cells. Moreover, silencing HO-1 prolonged the survival of xenograft mouse models. Further studies demonstrated that HO-1 suppressed the apoptosis of AML cells through activating the JNK/c-JUN signaling pathway. These data indicate a molecular role of HO-1 in inhibiting cell apoptosis, allowing it to be a potential target for treating AML.

Manu KA, Shanmugam MK, Ramachandran L, et al.
Isorhamnetin augments the anti-tumor effect of capeciatbine through the negative regulation of NF-κB signaling cascade in gastric cancer.
Cancer Lett. 2015; 363(1):28-36 [PubMed] Related Publications
Development of drug resistance to standard chemotherapy is a common phenomenon that leads to poor prognosis in patients. Thus, novel agents that can attenuate chemoresistance are urgently needed. Therefore, we analyzed whether isorhamnetin (IH), a 3'-O-methylated metabolite of quercetin, can enhance the potential efficacy of capecitabine in gastric cancer. The potential effect of IH on viability was analyzed by MTT assay, apoptosis by flow cytometric analysis, and NF-κB activation by DNA binding as well as Western blot assays. The in vivo effect of IH was also examined on the growth of subcutaneously implanted tumors in nude mice. IH inhibited the viability, potentiated the apoptotic effects of capecitabine, abrogated NF-κB activation, and suppressed the expression of various NF-κB regulated gene products in tumor cells. In a gastric cancer xenograft model, administration of IH alone (1 mg/kg body weight, i.p.) significantly suppressed the tumor growth alone as well as in combination with capecitabine. IH further reduced NF-κB activation and the expression of various proliferative and oncogenic biomarkers in tumor tissues. Overall, our results demonstrate that IH can significantly enhance the anti-tumor effects of capecitabine through the negative regulation of NF-κB regulated oncogenic genes.

François CM, Wargnier R, Petit F, et al.
17β-estradiol inhibits spreading of metastatic cells from granulosa cell tumors through a non-genomic mechanism involving GPER1.
Carcinogenesis. 2015; 36(5):564-73 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
Granulosa cell tumor (GCT) is a rare and severe form of sex-cord stromal ovarian tumor that is characterized by its long natural history and tendency to recur years after surgical ablation. Because there is no efficient curative treatment beyond surgery, ~20% of patients die of the consequences of their tumor. However, very little is known of the molecular etiology of this pathology. About 70% of GCT patients present with elevated circulating estradiol (E2). Because this hormone is known to increase tumor growth and progression in a number of cancers, we investigated the possible role of E2 in GCTs. Cell-based studies with human GCT metastases and primary tumor-derived cells, ie KGN and COV434 cells, respectively, aimed at evaluating E2 effect on cell growth, migration and invasion. Importantly, we found that E2 did not affect GCT cell growth, but that it significantly decreased the migration and matrix invasion of metastatic GCT cells. Noteworthy, our molecular studies revealed that this effect was accompanied by the inhibition through non-genomic mechanisms of extracellular signal-regulated kinase 1/2 (ERK1/2), which is constitutively activated in GCTs. By using pharmacological and RNA silencing approaches, we found that E2 action was mediated by G protein-coupled estrogen receptor 1 (GPER1) signaling pathway. Analyses of GPER1 expression on tissue microarrays from human GCTs confirmed its expression in ~90% of GCTs. Overall, our study reveals that E2 would act via non-classical pathways to prevent metastasis spreading in GCTs and also reveals GPER1 as a possible target in this disease.

Das S, Martinez LR, Ray S
Phospholipid remodeling and eicosanoid signaling in colon cancer cells.
Indian J Biochem Biophys. 2014; 51(6):512-9 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
Phospholipid remodeling and eicosanoid synthesis are central to lipid-based inflammatory reactions. Studies have revealed that membrane phospholipid remodeling by fatty acids through deacylation/reacylation reactions increases the risk of colorectal cancers (CRC) by allowing the cells to produce excess inflammatory eicosanoids, such as prostaglandins, thromboxanes and leukotrienes. Over the years, efforts have been made to understand the lipid remodeling pathways and to design anti-cancer drugs targeting the enzymes of eicosanoid biosynthesis. Here, we discuss the recent progress in phospholipid remodeling and eicosanoid biosynthesis in CRC.

Ray A, Alalem M, Ray BK
Insulin signaling network in cancer.
Indian J Biochem Biophys. 2014; 51(6):493-8 [PubMed] Related Publications
The primary function of insulin is viewed as a hormone that controls blood glucose level. However, there is growing evidence that aberrant insulin level and insulin-mediated signaling can lead to cancer development and progression. The insulin-cancer relationship has stemmed from various observational and epidemiological studies, which linked higher incidence of cancer with central obesity, type II diabetes and other conditions associated with increased levels of circulating insulin, insulin resistance and hyperinsulinemic states. Increased risk of developing a range of cancers is also seen with a certain treatment options used to lower blood glucose level in diabetic patients. While metformin monotherapy has the lowest risk of developing cancer, in comparison, treatment with insulin or insulin secretagogues shows more likelihood to develop solid cancers. Cellular signaling initiated by insulin provides a clue regarding these diverse cellular outcomes. This review discusses how the insulin enacts such diverse physiological effects and the insulin-cancer relationship, with focus on the role of insulin signaling in cancer.

Leung WK, He M, Chan AW, et al.
Wnt/β-Catenin activates MiR-183/96/182 expression in hepatocellular carcinoma that promotes cell invasion.
Cancer Lett. 2015; 362(1):97-105 [PubMed] Related Publications
Nearly 50% of known miRNAs are found in clusters and transcribed as polycistronic transcripts. In this study, we showed that over-expression of miR-183/96/182 cluster is frequent in hepatocellular carcinoma (HCC), a highly aggressive malignancy that is commonly fatal. In a cohort of HCC patients (n = 81), miR-183/96/182 up-regulation correlated with metastatic features including presence of microvascular invasion, advanced tumor differentiation, and shorter recurrence-free survival. Univariate and multivariate analyses further showed miR-183/96/182 over-expression represented an independent prognostic factor (Relative Risk: 2.0471; P = 0.0289). Functional investigation using siRNA against miR-183/96/182 in two invasive HCC cells indicated significant inhibition on cell migration and invasion without affecting cell viability. Forkhead boxO1 (FOXO1) was further validated as a downstream target of these three miRNAs. In investigating the regulatory mechanism underlining miR-183/96/182 over-expression, a direct interaction of CTNNB1 on the promoter region was confirmed by ChIP-PCR and luciferase reporter validations. Knockdown of CTNNB1 also showed concordant down-regulations of miR-183, -96 and -182, and the re-expression of FOXO1. Our findings demonstrated that over-expression of miR-183/96/182 confers an oncogenic function in HCC cell dissemination, and could serve as an independent prognostic predictor for HCC patients.

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