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

Autor: Ali Niapour, Naisana Seyedasli
Rok vydání: 2022
Předmět:
Zdroj: Naunyn-Schmiedeberg's Archives of Pharmacology. 395:515-533
ISSN: 1432-1912
0028-1298
DOI: 10.1007/s00210-022-02217-3
Popis: This study aims to develop a paclitaxel (PTX)-resistant gastric cancer AGS cells (AGS-R) and evaluate the mechanisms of drug resistance.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.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).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.
Databáze: OpenAIRE
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