RAB25 confers resistance to chemotherapy by altering mitochondrial apoptosis signaling in ovarian cancer cells
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RAB25 confers resistance to chemotherapy by altering mitochondrial apoptosis signaling in ovarian cancer cells Sehime Gulsun Temel1 · Aslı Giray2 · Bahriye Karakas3 · Ozgur Gul4 · Ilknur Kozanoglu5 · Husnu Celik6 · Huveyda Basaga3 · Ufuk Acikbas8 · Ceren Sucularli7 · Sidika Oztop8 · Yeliz Aka8 · Ozgur Kutuk8,9 Accepted: 1 September 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Ovarian cancer remains one of the most frequent causes of cancer-related death in women. Many patients with ovarian cancer suffer from de novo or acquired resistance to chemotherapy. Here, we report that RAB25 suppresses chemotherapy-induced mitochondrial apoptosis signaling in ovarian cancer cell lines and primary ovarian cancer cells. RAB25 blocks chemotherapyinduced apoptosis upstream of mitochondrial outer membrane permeabilization by either increasing antiapoptotic BCL-2 proteins or decreasing proapoptotic BCL-2 proteins. In particular, BAX expression negatively correlates with RAB25 expression in ovarian cancer cells. BH3 profiling assays corroborated that RAB25 decreases mitochondrial cell death priming. Suppressing RAB25 by means of RNAi or RFP14 inhibitory hydrocarbon-stapled peptide sensitizes ovarian cancer cells to chemotherapy as well as RAB25-mediated proliferation, invasion and migration. Our data suggest that RAB25 is a potential therapeutic target for ovarian cancer. Keywords RAB25 · Chemotherapy · Bcl-2 proteins · Ovarian cancer
Introduction Ovarian cancer remains one of the most frequent causes of cancer-related death in women with an estimated 22,240 new cases and 14,070 ovarian cancer deaths in US [1]. Inadequate population-based screening programs and lack of reliable biochemical markers for ovarian cancer results in Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10495-020-01635-z) contains supplementary material, which is available to authorized users. * Ozgur Kutuk [email protected] 1
diagnosis of most cases at later stages. In particular, serous ovarian cancers are diagnosed mostly at stage III or IV. Hence, 5-year survival of patients with stage III and stage IV high-grade serous ovarian carcinoma remains at 42% and 26%, respectively [1]. Therefore, developing targeted therapies to be used alone or in combination with conventional chemotherapy in ovarian cancer patients with advanced disease is a priority to reduce ovarian cancer mortality. Ras-associated binding protein 25 (RAB25, RAB11c, Catx8) small GTPase is a member of Rab family GTPases 6
Department of Obstetrics and Gynecology, Baskent University, Adana Dr. Turgut Noyan Medical and Research Center, Adana, Turkey
Department of Medical Genetics, School of Medicine, Uludag University, Bursa, Turkey
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Department of Genetics and Bioengineering, Alanya Alaaddin Keykubat University, Alanya, Turkey
Department of Bioinformatics, Institute of Health Sciences, Hacettepe University, Ankara, Turkey
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Molecular Biology, Genetics and Bioengineeri
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