Deregulation of Exo70 Facilitates Innate and Acquired Cisplatin Resistance in Epithelial Ovarian Cancer by Promoting Cisplatin Efflux

Abstract

Whilst researches elucidating a diversity of intracellular mechanisms, platinum-resistant epithelial ovarian cancer (EOC) remains a major challenge in the treatment of ovarian cancer. Here we report that Exo70, a key subunit of the exocyst complex, contributes to both innate and acquired cisplatin resistance of EOC. Upregulation of Exo70 is observed in EOC tissues and is related to platinum resistance and progression-free survival of EOC patients. Exo70 suppressed the cisplatin sensitivity of EOC cells through promoting exocytosis-mediated efflux of cisplatin. Moreover, cisplatin-induced autophagy-lysosomal degradation of Exo70 protein by modulating phosphorylation of AMPK and mTOR, thereby reducing the cellular resistance. However, the function was hampered during prolonged cisplatin treatment, which in turn stabilized Exo70 to facilitate the acquired cisplatin resistance of EOC cells. Knockdown of Exo70, or inhibiting exocytosis by Exo70 inhibitor Endosidin2, reversed the cisplatin resistance of EOC cells both in vitro and in vivo. Our results suggest that Exo70 overexpression and excessive stability contribute to innate and acquired cisplatin resistance through the increase in cisplatin efflux, and targeting Exo70 might be an approach to overcome cisplatin resistance in EOC treatment.

FGF19 promotes cell autophagy and cisplatin chemoresistance by activating MAPK signaling in ovarian cancer

“…Furthermore, as promising regulators of autophagy, the non-coding RNAs, such as lncRNAs and miRNAs, can regulate therapeutic resistance in cancer cells ( Eng et al, 2021 ; Hou, Li & Dong, 2021 ; Xia et al, 2022 ). Moreover, increasing studies have confirmed that autophagy is involved in the progression and drug resistance of ovarian cancer cells ( Zhao et al, 2021 ). In addition, FGF family members display important effects in the regulation of cell autophagy.…”

Exo70 promotes herpesvirus secretory vesicle tethering and virion release in an exocyst complex-dependent manner

“…Endosidin2 (ES2) was identified through plant-based chemical screening as a transport inhibitor that combines with the Exo70 subunit to terminate the final stage of exocytosis [17, 37]. ES2 treatment can effectively improve the cisplatin sensitivity of acquired cisplatin resistant epithelial ovarian cancer cells, and can be used as a potential drug for the treatment of epithelial ovarian cancer [38]. In addition, ES2 treatment can lead to impaired transport of GLUT4 to the PM and hinder glucose uptake under insulin stimulation [39].…”

Autophagy and necroptosis in cisplatin-induced acute kidney injury: Recent advances regarding their role and therapeutic potential

“…In lung cancer, Sirichanchuen et al (2012) demonstrated that long-term exposure to CP impaired autophagy leading to CP resistance, and interestingly, upregulation of autophagic response under such condition re-sensitized resistant cells to CP-induced cell death. In addition, autophagic degradation of Exo70 reduced CP efflux, thereby increasing its intracellular storage and cytotoxic activity ( Zhao et al, 2021 ). Moreover, it has been reported that induction of autophagy helps to overcome CP resistance and potentiates its cytotoxic activity against lung cancer ( Cheng et al, 2019 ; López-Plana et al, 2020 ), and oral cancer ( Gao et al, 2022 ).…”