ARL6IP5 reduces cisplatin-resistance by suppressing DNA repair and promoting apoptosis pathways in ovarian carcinoma

Ji Ye Kim, Entaz Bahar, Jung Yun Lee, Sunhee Chang, Se Hoon Kim, Eun Young Park, Sung Im Do, Hyonok Yoon, Hyun Soo Kim

Research output: Contribution to journalArticlepeer-review

Abstract

Ovarian carcinoma (OC) is the most lethal gynecological malignancy due to frequent recurrence resulting from cisplatin-resistance. ARL6IP5 is a novel gene implicated to suppress cisplatin-resistance by activating apoptosis and inhibiting DNA repair through XRCC1 and PARP1. We investigated the clinicopathological and prognostic significance of the immunohistochemical ARL6IP5 expression on 79 post-chemotherapy OC patient tissue samples; in vitro, the effect of ARL6IP5 overexpression (OE) and knockdown (KD) on cancer hallmark functions and the effect of ARL6IP5 on the expression of DNA repair and apoptosis-related proteins were observed in OC cells and their cisplatin-resistant (CisR) counterparts. ARL6IP5 expression was significantly associated with chemotherapeutic response and was an independent prognosticator of progression-free and overall survival of high-grade serous OC patients. ARL6IP5-OE decreased cellular proliferation, invasion, migration, adhesion, and increased apoptosis (p < 0.05); the opposite was observed for ARL6IP5-KD. Notably, ARL6IP5-OE reduced cisplatin-resistance of both OC and CisR OC cells, while ARL6IP5-KD increased cisplatin-resistance (p < 0.05). ARL6IP5-OE suppressed the expressions of DNA repair proteins and increased those of pro-apoptotic proteins; the opposite was observed for ARL6IP5-KD. The recombinant ARL6IP5 protein (rARL6IP5) had the greatest apoptotic effect among cisplatin and olaparib, in both OC and CisR OC cells; moreover, rARL6IP5 was the only single agent in CisR OC cells to retain higher apoptotic efficacy compared with control (p < 0.05), indicating that the apoptotic pathway influenced by rARL6IP5 remained effective in CisR OC cells compared to cisplatin and olaparib. In conclusion, we demonstrated that ARL6IP5 is an independent prognosticator of OC patients with cellular functions of a tumor-suppressor, possibly influencing the development of cisplatin-resistance and progression of OC cells through regulation of DNA repair and apoptosis. rARL6IP5 had significantly greater apoptotic efficacy compared to conventional chemotherapeutic agents in both OC and CisR OC cells, suggesting that ARL6IP5 may be a valuable novel chemotherapeutic against CisR OC.

Original languageEnglish
Article number239
JournalCell Death and Disease
Volume13
Issue number3
DOIs
Publication statusPublished - 2022 Mar

Bibliographical note

Funding Information:
This work was supported in part by the Career Development Award in National Cancer Center Korea (NCCCDA2018-04), the Korea Health Industry Development Institute (HI21C1137), the National Research Foundation of Korea (NRF) grant funded by the Korean government (Ministry of Science and ICT) (2018R1C1B5043725, 2019R1F1A1059148, 2022R1A2C1009939, and 2022R1C1C1008833) and the Basic Science Research Program through the NRF funded by the Ministry of Education (2016R1D1A1B03935584).

Publisher Copyright:
© 2022, The Author(s).

All Science Journal Classification (ASJC) codes

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

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