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KMID : 0624620190520090566
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BMB Reports
2019 Volume.52 No. 9 p.566 ~ p.571
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ACOX1 destabilizes p73 to suppress intrinsic apoptosis pathway and regulates sensitivity to doxorubicin in lymphoma cells
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Zheng Fei-Meng
Chen Wang-Bing
Qin Tao
Lv Li-Na
Feng Bi
Lu Yan-Ling
Li Zuo-Quan
Wang Xiao-Chao
Tao Li-Ju
Li Hong-Wen
Li Shu-You
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Abstract
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Lymphoma is one of the most curable types of cancer. However, drug resistance is the main challenge faced in lymphoma treatment. Peroxisomal acyl-CoA oxidase 1 (ACOX1) is the rate-limiting enzyme in fatty acid β-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 mitochondrial location of Bad, 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 decrease 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. Also, overexpression of ACOX1 significantly reduced stability of p73 protein thereby reducing p73 expression. Thus, our study indicated that suppression of ACOX1 could be a novel and effective approach for treatment of lymphoma.
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KEYWORD
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ACOX1, Apoptosis, Doxorubicin, Drug resistance, Lymphoma, p73, Protein degradation
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