Abstract
BackgroundSeveral 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. .ResultsWe 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.ConclusionsThese 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.
Highlights
Several reports indicated that the expression of Yes-associated protein (YAP) was associated with multi-drug resistance
YAP is highly expressed in epithelial ovarian carcinoma (EOC) and is directly regulated by V-ATPase D1 expression We found that both V-ATPase D1 and YAP were overexpressed in EOC tissues
Since V-ATPase D1 expression was increased in PTX-resistant EOC cells, we examined the effect of V-ATPase D1 silencing on YAP levels in PTXresistant A2780/T cells
Summary
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 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. The acidic microenvironment increased by overexpression of V-ATPases is observed in tumor growth, metastasis and chemoresistance [9]. Several studies have demonstrated that PPIs (proton pump inhibitors), which directly inhibit V-ATPase at the cellular level, has reverted chemoresistance of drug-resistant tumors [10,11,12].
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