Several reports indicated that the expression of Yes-associated protein (YAP) was associated with multi-drug resistance. Acidic microenvironment increased by the overexpression of vacuolar-ATPase (V-ATPase) was also observed in tumor growth and drug resistance. We hypothesize that proton pump inhibitors (PPIs), currently used in the anti-acid treatment of peptic disease, could inhibit the acidification of the tumor microenvironment and increase the sensitivity of tumor cells to cytotoxic agents. Thus, our objective is to explore the reversal of drug resistance by the inhibition of YAP through specific PPIs in the epithelial ovarian carcinoma (EOC) cells. . We found that V-ATPase D1 was a positive regulator of YAP. Sub-lethal doses of the proton pump inhibitor esomeprazole (EMSO) in combination with paclitaxel (PTX) increased the PTX sensitivity in PTX-resistant EOC cells, as compared to PTX single treatments by inhibiting YAP and reserving pH gradient created by the V-ATPase D1. Moreover, sub-lethal doses of EMSO combined with PTX decreased autophagy and improved caspases independent apoptosis of PTX-resistant EOC cells. These results suggested that sub-lethal doses of esomeprazole reverse YAP-mediated PTX resistance through the inhibiting of both YAP expression and acidic tumor microenvironment created by the V-ATPase D1. Therefore, we think the use of PPIs represents a promising strategy to improve the effectiveness of anti-EOC.

中文翻译：

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质子泵抑制剂可逆转YAP介导的上皮性卵巢癌紫杉醇耐药性

几篇报道指出，Yes相关蛋白（YAP）的表达与多药耐药性有关。在肿瘤生长和耐药性中也观察到液泡ATP酶（V-ATPase）过表达增加的酸性微环境。我们假设当前用于抗消化性疾病的抗酸治疗的质子泵抑制剂（PPI）可以抑制肿瘤微环境的酸化并增加肿瘤细胞对细胞毒剂的敏感性。因此，我们的目标是探索通过上皮性卵巢癌（EOC）细胞中特定PPI抑制YAP来逆转耐药性。。我们发现V-ATPase D1是YAP的正调节剂。与PTX单药治疗相比，通过抑制YAP并保留由V-ATPase产生的pH梯度，与PTX单药治疗相比，亚致死剂量的质子泵抑制剂埃索美拉唑（EMSO）与紫杉醇（PTX）组合提高了PTX耐药性EOC细胞的PTX敏感性。 D1 此外，亚致死剂量的EMSO与PTX结合可减少自噬，并改善半胱氨酸蛋白酶对PTX耐药EOC细胞的独立凋亡。这些结果表明，亚致死剂量的埃索美拉唑通过抑制YAP表达和由V-ATPase D1产生的酸性肿瘤微环境来逆转YAP介导的PTX耐药性。因此，我们认为使用PPI是提高抗EOC效力的一种有前途的策略。与PTX单一处理相比，可抑制YAP并保留由V-ATPase D1产生的pH梯度。此外，亚致死剂量的EMSO与PTX结合可减少自噬，并改善半胱氨酸蛋白酶对PTX耐药EOC细胞的独立凋亡。这些结果表明，亚致死剂量的埃索美拉唑通过抑制YAP表达和由V-ATPase D1产生的酸性肿瘤微环境来逆转YAP介导的PTX耐药性。因此，我们认为使用PPI是提高抗EOC效力的一种有前途的策略。与PTX单处理相比，通过抑制YAP并保留由V-ATPase D1产生的pH梯度。此外，亚致死剂量的EMSO与PTX结合可减少自噬，并改善半胱氨酸蛋白酶对PTX耐药EOC细胞的独立凋亡。这些结果表明，亚致死剂量的埃索美拉唑通过抑制YAP表达和由V-ATPase D1产生的酸性肿瘤微环境来逆转YAP介导的PTX耐药性。因此，我们认为使用PPI是提高抗EOC效力的一种有前途的策略。这些结果表明，亚致死剂量的埃索美拉唑通过抑制YAP表达和由V-ATPase D1产生的酸性肿瘤微环境来逆转YAP介导的PTX耐药性。因此，我们认为使用PPI是提高抗EOC效力的一种有前途的策略。这些结果表明，亚致死剂量的埃索美拉唑通过抑制YAP表达和由V-ATPase D1产生的酸性肿瘤微环境来逆转YAP介导的PTX耐药性。因此，我们认为使用PPI是提高抗EOC效力的一种有前途的策略。