PMID- 35293383 OWN - NLM STAT- MEDLINE DCOM- 20220408 LR - 20221211 IS - 2041-4889 (Electronic) VI - 13 IP - 3 DP - 2022 Mar 15 TI - ARL6IP5 reduces cisplatin-resistance by suppressing DNA repair and promoting apoptosis pathways in ovarian carcinoma. PG - 239 LID - 10.1038/s41419-022-04568-4 [doi] LID - 239 AB - 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. CI - (c) 2022. The Author(s). FAU - Kim, Ji-Ye AU - Kim JY AUID- ORCID: 0000-0003-4291-2967 AD - Department of Pathology, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea. AD - Department of Pathology, Yonsei University College of Medicine, Seoul, Korea. AD - Department of Pathology, National Cancer Center, Goyang, Korea. FAU - Bahar, Entaz AU - Bahar E AUID- ORCID: 0000-0002-4403-7978 AD - Department of Convergence Medical Science and Biochemistry, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Korea. AD - College of Pharmacy, Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju, Korea. FAU - Lee, Jung-Yun AU - Lee JY AD - Department of Obstetrics and Gynecology, Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Korea. FAU - Chang, Sunhee AU - Chang S AD - Department of Pathology, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea. AD - Department of Pathology, National Cancer Center, Goyang, Korea. FAU - Kim, Se Hoon AU - Kim SH AUID- ORCID: 0000-0001-7516-7372 AD - Department of Pathology, Yonsei University College of Medicine, Seoul, Korea. FAU - Park, Eun Young AU - Park EY AD - Biostatistics Collaboration Team, Research Core Center, National Cancer Center, Goyang, Korea. FAU - Do, Sung-Im AU - Do SI AD - Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea. FAU - Yoon, Hyonok AU - Yoon H AUID- ORCID: 0000-0001-7945-5590 AD - College of Pharmacy, Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju, Korea. hoyoon@gnu.ac.kr. FAU - Kim, Hyun-Soo AU - Kim HS AUID- ORCID: 0000-0003-4730-221X AD - Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. hyun-soo.kim@samsung.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220315 PL - England TA - Cell Death Dis JT - Cell death & disease JID - 101524092 RN - 0 (ARL6IP5 protein, human) RN - 0 (Antineoplastic Agents) RN - 0 (Heat-Shock Proteins) RN - 0 (Membrane Transport Proteins) RN - 0 (X-ray Repair Cross Complementing Protein 1) RN - 0 (XRCC1 protein, human) RN - Q20Q21Q62J (Cisplatin) SB - IM MH - *Antineoplastic Agents/pharmacology/therapeutic use MH - Apoptosis MH - *Carcinoma/genetics MH - Carcinoma, Ovarian Epithelial/genetics MH - Cell Line, Tumor MH - Cisplatin/metabolism/pharmacology/therapeutic use MH - DNA Repair MH - Drug Resistance, Neoplasm/genetics MH - Female MH - Gene Expression Regulation, Neoplastic MH - Heat-Shock Proteins/*metabolism MH - Humans MH - Membrane Transport Proteins/*metabolism MH - *Ovarian Neoplasms/drug therapy/genetics/pathology MH - X-ray Repair Cross Complementing Protein 1/genetics PMC - PMC8924236 COIS- The authors declare no competing interests. EDAT- 2022/03/17 06:00 MHDA- 2022/04/09 06:00 PMCR- 2022/03/15 CRDT- 2022/03/16 08:44 PHST- 2021/01/16 00:00 [received] PHST- 2022/01/20 00:00 [accepted] PHST- 2021/12/31 00:00 [revised] PHST- 2022/03/16 08:44 [entrez] PHST- 2022/03/17 06:00 [pubmed] PHST- 2022/04/09 06:00 [medline] PHST- 2022/03/15 00:00 [pmc-release] AID - 10.1038/s41419-022-04568-4 [pii] AID - 4568 [pii] AID - 10.1038/s41419-022-04568-4 [doi] PST - epublish SO - Cell Death Dis. 2022 Mar 15;13(3):239. doi: 10.1038/s41419-022-04568-4.