Role of FAK, dominant-negative FAK, FAK-CD and FAKsiRNA in MCF-7 human breast cancer cell tumorigenesis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE11581 | GEO | 2009/08/17
SECONDARY ACCESSION(S): PRJNA106211
REPOSITORIES: GEO
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Project description:Chronic stress is associated with hormonal alterations that are known to promote cancer progression. The stress hormone norepinephrine promotes migration and metastasis of prostate cancer cells. Focal adhesion kinase (FAK) is a non-receptor protein tyrosine kinase which is phosphorylated during chronic stress or norepinephrine treatment. Here, we investigated how norepinephrine modulates the gene expression in Myc-CaP prostate cancer cell line. We also focused on the effect of FAK knockdown in norepinephrine-induced changes of the gene expression profile.
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Project description:Gastric cancer (GC) is one of the most common malignant neoplasms. Invasion and metastasis are the main causes of GC-related deaths. Recently, kinesins were discovered to be involved in tumor development. The aim of this study was to elucidate the roles of kinesin superfamily protein 26A (KIF26A) in GC and its underlying molecular mechanism in regulating tumor invasion and metastasis. Using real-time quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC), we showed that KIF26A expression was lower in GC tissues without lymph node metastasis (LNM) than in nontumorous gastric mucosa, and even lower in GC tissues with LNM than in GC tissues without LNM. Functional experiments showed that KIF26A inhibited migration and invasion of GC cells. We further identifified focal-adhesion kinase (FAK), phosphatidylinositol 3-kinase regulatory subunit alpha (PI3KR1), VAV3, Rac1 and p21-activated kinase 2, and β-PAK (PAK3) as downstream effectors of KIF26A in the focal-adhesion pathway, and we found that KIF26A could regulate FAK mRNA expression through inhibiting c-MYC by MAPK pathway. c-MYC could bind to the promoter of FAK and activate FAK transcription. Moreover, we found that KIF26A mediated inactivation of the focal-adhesion pathway could reduce the occurrence of the epithelial-to-mesenchymal transition (EMT) by increasing expression of E-cadherin and reducing that of Snail. Luciferase assays and Western blotting revealed that miR-19a and miR-96 negatively regulate KIF26A. Finally, we found that decreased expression of KIF26A has been positively correlated with histological differentiation, Lauren classifification, LNM, distal metastasis, and clinical stage, as well as poor survival in patients with GC. These data indicate that KIF26A could inhibit GC migration and invasion by regulating the focal adhesion pathway and repressing the occurrence of EMT.
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Project description:Mutated KRAS serves as the oncogenic driver in 30% of non-small cell lung cancers (NSCLCs) and is associated with metastatic and therapy-resistant tumors. Focal Adhesion Kinase (FAK) acts as a mediator in sustaining KRAS-driven lung tumors, and although FAK inhibitors are currently undergoing clinical development, clinical data indicated that their efficacy in producing long-term anti-tumor responses is limited. Here we revealed two FAK interactors, extracellular-signal-regulated kinase 5 (ERK5) and cyclin-dependent kinase 5 (CDK5) as key players underlying FAK-mediated maintenance of KRAS mutant NSCLC. Inhibition of ERK5 and CDK5 synergistically suppressed FAK function, decreased proliferation and induced apoptosis owing to exacerbated ROS-induced DNA damage. Accordingly, concomitant pharmacological inhibition of ERK5 and CDK5 in a mouse model of KrasG12D-driven lung adenocarcinoma suppressed tumor progression and promoted cancer cell death. Cancer cells resistant to FAK inhibitors showed enhanced ERK5-FAK signaling dampening DNA damage. Notably, ERK5 inhibition prevents resistance to FAK inhibitors, significantly enhancing the efficacy of antitumor responses. Therefore, we propose ERK5 inhibition as a potential co-targeting strategy to counteract FAK inhibitor resistance in NSCLC.
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Project description:Mutated KRAS serves as the oncogenic driver in 30% of non-small cell lung cancers (NSCLCs) and is associated with metastatic and therapy-resistant tumors. Focal Adhesion Kinase (FAK) acts as a mediator in sustaining KRAS-driven lung tumors, and although FAK inhibitors are currently undergoing clinical development, clinical data indicated that their efficacy in producing long-term anti-tumor responses is limited. Here we revealed two FAK interactors, extracellular-signal-regulated kinase 5 (ERK5) and cyclin-dependent kinase 5 (CDK5) as key players underlying FAK-mediated maintenance of KRAS mutant NSCLC. Inhibition of ERK5 and CDK5 synergistically suppressed FAK function, decreased proliferation and induced apoptosis owing to exacerbated ROS-induced DNA damage. Accordingly, concomitant pharmacological inhibition of ERK5 and CDK5 in a mouse model of KrasG12D-driven lung adenocarcinoma suppressed tumor progression and promoted cancer cell death. Cancer cells resistant to FAK inhibitors showed enhanced ERK5-FAK signaling dampening DNA damage. Notably, ERK5 inhibition prevents resistance to FAK inhibitors, significantly enhancing the efficacy of antitumor responses. Therefore, we propose ERK5 inhibition as a potential co-targeting strategy to counteract FAK inhibitor resistance in NSCLC.
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Project description:Breast and pancreatic cancers are characterised by profound metabolic changes1,2. Until recently, these changes have been ascribed to their intrinsic genetic profiles2-4. However, the contribution of cancer-associated fibroblasts (CAFs) to cell metabolism has not been fully investigated5. Here, we provide clinical evidence that reduction in stromal Focal Adhesion Kinase (FAK) correlates with reduced overall survival in human breast and pancreatic cancer patients. To model this, we developed FSP-Cre+;FAKfl/fl mice where FAK was deleted in a subpopulation of CAFs. We establish that loss of CAF-FAK is sufficient to enhance tumour growth without affecting desmoplasia in orthotopically injected breast and pancreatic carcinomas. Additionally, deletion of CAF-FAK enhances disease progression in the MMTV-PyMT spontaneous model of breast cancer. Furthermore, despite this pro-tumourigenic effect, a significant reduction in tumour angiogenesis was observed in late-stage tumours, but not early-stage, size-matched tumours in FSP-Cre+;FAKfl/fl mice. This indicates that loss of CAF-FAK is sufficient to reduce malignant cell dependency on blood vessel support suggesting acquired metabolic alterations in cancer cells. Indeed, 18F-FDG-PET imaging and glucose flux analysis revealed enhanced glucose catabolism in early-stage, size-matched tumours in FSP-Cre+;FAKfl/fl mice in vivo. Mechanistically, we demonstrate that conditioned medium from FAK-null CAFs enhances glycolysis and glycolytic capacity in malignant cells. Proteomics and phosphoproteomics analysis reveal enriched cytokine-mediated signalling pathways in FAK-null CAFs and subsequent enrichment of associated phosphopeptides in malignant cells, respectively. Overall, our data uncover a novel mechanism by which cytokines, regulated by CAF-FAK, can promote cancer growth and progression, and identify a new set of CAF-derived targets to interfere with cancer metabolism.
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