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As a partner of tetraspanins, EWI2 suppresses glioblastoma, melanoma, and prostate cancer; but its role in lung cancer has not been investigated. Bioinformatics analysis reveals that EWI2 gene expression is up regulated in lung adenocarcinoma and higher expression of EWI2 mRNA may predict poorer overall survival. However, experimental analysis shows that EWI2 protein is actually downregulated constantly in the tissues of lung adenocarcinoma and lung squamous cell carcinoma. Forced expression of EWI2 in human lung adenocarcinoma cells reduces total cellular and cell surface levels of various integrins and growth factor receptors, which initiates the outside-in motogenic and mitogenic signaling. These reductions result in the decreases in 1) cell-matrix adhesion, cell movement, and cell transformation in vitro and 2) tumor growth, burden, and metastasis in vivo, and result from the increases in lysosomal trafficking and proteolytic degradation of theses membrane receptors. EWI2 elevates lysosome formation by promoting nuclear retention of TFEB, the master transcription factor driving lysosomogenesis. In conclusion, EWI2 as a lung cancer suppressor attenuates lung cancer cells in a comprehensive fashion by inhibiting both tumor growth and tumor metastasis; EWI2 as an endolysosome regulator promotes lysosome activity to enhance lysosomal degradation of growth factor receptors and integrins and then reduce their levels and functions; and EWI2 can become a promising therapeutic candidate given its accessibility at the cell surface, dual inhibition on growth factor receptors and integrins, and broad-spectrum anti-cancer activity. More importantly, our observations also provide a novel therapeutic strategy to bypass the resistance to EGFR inhibitors. more...

Pancreatic cancer is among the most aggressive human cancers, and is resistant to regular chemotherapy and radiotherapy. The AT-rich interactive domain containing protein 1A (ARID1A) gene, a crucial chromatin remodeling gene, mutates frequently in a broad spectrum of cancers, including pancreatic cancer. Recent evidence suggests that ARID1A acts as tumor suppressor and plays an important role in DNA damage repair (DDR). However, the effect of ARID1A on the radiosensitivity of pancreatic cancer remains unclear. Herein, we investigated the involvement of ARID1A depletion in the radioresistance of pancreatic cancer cells, and explored the underlying mechanisms. The results reveal that knockdown of ARID1A enhances the radioresistance of pancreatic cancer cells through suppressing apoptosis, impairing G2-M checkpoint arrest, strengthening DDR, and accompanying activation of PI3K/AKT signaling pathway. Moreover, upon inhibition of PI3K/AKT pathway by PI3K-inhibitor LY294002 or AKT-inhibitor mk2206, the radiosensitivity of ARID1A-deficient pancreatic cancer cells is improved in vitro via increased apoptosis and weakened DDR. Taken together, these data suggest that loss of ARID1A expression enhances radioresistance of pancreatic cancer through activation of PI3K/AKT pathway, which maybe a promising target for radiosensitization of ARID1A-deficient pancreatic cancer. more...

Dual blockade of phosphoinositide 3-kinase (PI3K) and poly(ADP-ribose) polymerase (PARP) has been revealed to be an effective treatment strategy for breast, ovarian and prostate cancer. However, the efficacy of this combination for the treatment of gastric cancer, and potential predictive therapeutic biomarkers remain unclear. Recent evidence suggests that the deficiency of AT-rich interactive domain containing protein 1A (ARID1A), which is a crucial chromatin remodeling gene, sensitizes tumor cells to PI3K and PARP inhibitors. Herein, we evaluated the therapeutic role of the combined treatment of PI3K inhibitor BKM120 and PARP inhibitor olaparib on gastric cancer cells, and explored ARID1A as a predictive biomarker. The results demonstrated that combined treatment with PI3K and PARP inhibitors effectively inhibited proliferation detected by MTS and clonogenic assay, invasion and migration by Transwell assay, of gastric cancer cells with ARID1A deficiency. Mechanistically, dual blockade of PI3K and PARP in ARID1A-depleted gastric cancer cells significantly increased apoptosis detected by flow cytometry, and induced DNA damage by immunofluorescent staining. Taken together, these data suggest that the combined treatment with PI3K inhibitor BKM120 and PARP inhibitor olaparib may be a promising therapeutic regimen for the treatment of gastric cancer, and ARID1A deficiency could serve as a potential predictive therapeutic biomarker. more...