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Article

The Mitochondrial PHB2/OMA1/DELE1 Pathway Cooperates with Endoplasmic Reticulum Stress to Facilitate the Response to Chemotherapeutics in Ovarian Cancer

Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China
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Authors to whom correspondence should be addressed.
Academic Editor: Stamatios E. Theocharis
Int. J. Mol. Sci. 2022, 23(3), 1320; https://doi.org/10.3390/ijms23031320
Received: 17 December 2021 / Revised: 12 January 2022 / Accepted: 17 January 2022 / Published: 25 January 2022
(This article belongs to the Special Issue Molecular Advances in Cancer Therapy)
Interactions between the mitochondrial inner and outer membranes and between mitochondria and other organelles closely correlates with the sensitivity of ovarian cancer to cisplatin and other chemotherapeutic drugs. However, the underlying mechanism remains unclear. Recently, the mitochondrial protease OMA1, which regulates internal and external signals in mitochondria by cleaving mitochondrial proteins, was shown to be related to tumor progression. Therefore, we evaluated the effect of OMA1 on the response to chemotherapeutics in ovarian cancer cells and the mouse subcutaneous tumor model. We found that OMA1 activation increased ovarian cancer sensitivity to cisplatin in vivo and in vitro. Mechanistically, in ovarian cancer, OMA1 cleaved optic atrophy 1 (OPA1), leading to mitochondrial inner membrane cristae remodeling. Simultaneously, OMA1 induced DELE1 cleavage and its cytoplasmic interaction with EIF2AK1. We also demonstrated that EIF2AK1 cooperated with the ER stress sensor EIF2AK3 to amplify the EIF2S1/ATF4 signal, resulting in the rupture of the mitochondrial outer membrane. Knockdown of OMA1 attenuated these activities and reversed apoptosis. Additionally, we found that OMA1 protease activity was regulated by the prohibitin 2 (PHB2)/stomatin-like protein 2 (STOML2) complex. Collectively, OMA1 coordinates the mitochondrial inner and outer membranes to induce ovarian cancer cell death. Thus, activating OMA1 may be a novel treatment strategy for ovarian cancer. View Full-Text
Keywords: OMA1; ovarian cancer; DELE1; mitochondrial membranes; endoplasmic reticulum stress OMA1; ovarian cancer; DELE1; mitochondrial membranes; endoplasmic reticulum stress
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MDPI and ACS Style

Cheng, M.; Yu, H.; Kong, Q.; Wang, B.; Shen, L.; Dong, D.; Sun, L. The Mitochondrial PHB2/OMA1/DELE1 Pathway Cooperates with Endoplasmic Reticulum Stress to Facilitate the Response to Chemotherapeutics in Ovarian Cancer. Int. J. Mol. Sci. 2022, 23, 1320. https://doi.org/10.3390/ijms23031320

AMA Style

Cheng M, Yu H, Kong Q, Wang B, Shen L, Dong D, Sun L. The Mitochondrial PHB2/OMA1/DELE1 Pathway Cooperates with Endoplasmic Reticulum Stress to Facilitate the Response to Chemotherapeutics in Ovarian Cancer. International Journal of Molecular Sciences. 2022; 23(3):1320. https://doi.org/10.3390/ijms23031320

Chicago/Turabian Style

Cheng, Meiyu, Huimei Yu, Qinghuan Kong, Bingrong Wang, Luyan Shen, Delu Dong, and Liankun Sun. 2022. "The Mitochondrial PHB2/OMA1/DELE1 Pathway Cooperates with Endoplasmic Reticulum Stress to Facilitate the Response to Chemotherapeutics in Ovarian Cancer" International Journal of Molecular Sciences 23, no. 3: 1320. https://doi.org/10.3390/ijms23031320

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