ایجاد مقاومت نسبت به پاکلی تاکسول صفات بیولوژیکی سلول های AGS سرطان معده را تغییر داده و قابلیت انتقال از حالت اپیتلیالی به مزانشیمی و آنژیوژنز را تسهیل می کند

عنوان انگليسی

Acquisition of paclitaxel resistance modulates the biological traits of gastric cancer AGS cells and facilitates epithelial to mesenchymal transition and angiogenesis

خلاصه انگلیسی

Purpose This study aims to develop a paclitaxel (PTX)-resistant gastric cancer AGS cells (AGS-R) and evaluate the mechanisms of drug resistance. Methods AGS cells were successively treated with increasing PTX concentrations. Cross-resistance of established AGS-R, the molecular patterns of cell survival, evasion of apoptosis, epithelial-mesenchymal transition (EMT), and the angiogenic potential were evaluated. Results AGS-R was induced within six months of PTX exposure. Extension of the treatment resulted in PTX-resistance beyond clinical levels. The established AGS-R showed resistance to vincristine and doxorubicin but not cisplatin. Upon induction of resistance, the expressions of MDR-1 (P < 0.001) and MRP-1 (P < 0.01) genes and proteins significantly increased. AGS-R cells had elevated levels of BCL-2, pro-CASP3, cleaved-NOTCH1, HES1, HEY1, NF-κB, PI3K, p-AKT, HIF-1α, Cyclin A, and B1 as compared with parental cells (at least P < 0.01). The protein levels of BAX, CASP3, P53, and P21 (at least P < 0.01) as well as intracellular ROS (P < 0.001) were reduced in AGS-R. A relative arrest at the G2/M phase (15.8 ± 0.75 vs. 26.7 ± 1.67) of the cell cycle and enrichment of AGS-R cells for CD44 marker (9 ± 0.6 vs. 1 ± 0.8) (P < 0.001) were detected by flow cytometry. While the E-cadherin expression was reduced (P < 0.001), the protein levels of Vimentin, N-cadherin, SLUG, and SNAIL were increased (at least P < 0.05). The angiogenic activity and release of VEGF and MMP2/9 were increased in AGS-R cells relative to the AGS line (P < 0.001). Conclusion AGS-R cells could bypass chemotherapy stress by expressing the genes coding for efflux pumps and altering some key signaling in favor of survival, EMT, and angiogenesis.

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