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ACOX1 destabilizes p73 to suppress intrinsic apoptosis pathway and regulates sensitivity to doxorubicin in lymphoma cells.
Fei-Meng Zheng1,2,*, Wang-Bing Chen3, Tao Qin4, Li-Na Lv5, Bi Feng1, Yan-Ling Lu1, Zuo-Quan Li6, Xiao-Chao Wang7, Li-Ju Tao5, Hong-Wen Li5, Shu-You Li8
1Department of Medical Oncology of The Eastern Hospital and 2Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, The First Affiliated Hospital, Sun Yat-sen University,
3Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology,
4Department of Medical Oncology, Sun Yat-sen Hospital, Sun Yat-sen University,
5Department of Hematology, Wuming Hospital of Guangxi Medical University,
6Department of Ultrasound, Guancheng Hospital,
7Department of Hematology, Affiliated Hospital of Youjiang Medical University for Nationalities,
8Department of Medical Oncology, Wuming Hospital of Guangxi Medical University
Abstract
lymphoma is one of the most curable types of cancer. However, drug resistance is still the main challenge faced in lymphoma treatment. Peroxisomal acyl-CoA oxidase 1 (ACOX1) is the rate-limiting enzyme in fatty acid モ-oxidation. Deregulation of ACOX1 has been linked to peroxisomal disorders and carcinogenesis in the liver. Currently, there is no information about the function of ACOX1 in lymphoma. In this study, we found that upregulation of ACOX1 promoted proliferation in lymphoma cells, while downregulation of ACOX1 inhibited proliferation and induced apoptosis. Additionally, overexpression of ACOX1 increased resistance to doxorubicin, while suppression of ACOX1 expression markedly potentiated doxorubicin-induced apoptosis. Interestingly, downregulation of ACOX1 promoted Bad mitochondrial location, reduced mitochondrial membrane potential and provoked apoptosis by activating caspase-9 and caspase-3 related apoptotic pathway. Overexpression of ACOX1 alleviated doxorubicin-induced activation of caspase-9 and caspase-3 and decreasing of mitochondrial membrane potential. Importantly, downregulation of ACOX1 increased p73, but not p53, expression. p73 expression was critical for apoptosis induction induced by ACOX1 downregulation. Moreover, overexpression of ACOX1 significantly reduced the stability of p73 protein thereby reducing p73 expression. Thus, our study indicated that suppression of ACOX1 could be a novel and effective approach for the treatment of lymphoma.
Abstract, Accepted Manuscript(in press) [Submitted on March 30, 2019, Accepted on July 17, 2019]
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