ALOX12 inhibition sensitizes breast cancer to chemotherapy via AMPK activation and inhibition of lipid synthesis.

Affiliation

Department of Breast Surgery, the Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, China. Electronic address: [Email]

Abstract

Arachidonate lipoxygenase12 (Alox12) and its metabolites 12S-hydroxyeicosatetraenoic acid (12S-HETE) have been implicated in influencing tumor transformation and progression. In this study, we have systematically evaluated the expression, function and the downstream effectors of Alox12 in breast cancer using loss- and gain-of-function approaches. We demonstrated that both mRNA and protein levels of Alox12 were significantly increased in multiple breast cancer cell lines compared to normal breast cells. The upregulation of Alox12 expression was also observed in breast cancer tissues and their matched normal breast tissues obtained from patients. Functionally, we demonstrated that Alox12 overexpression was sufficient to stimulate growth in normal breast cells but not breast cancer cells. This also protects breast cancer cell from chemotherapy-induced growth arrest and apoptosis. In contrast, Alox12 depletion inhibited breast cancer growth and survival, and significantly enhanced the chemotherapeutic agents' efficacy. Mechanism studies showed that Alox12 depletion activated AMP-activated protein kinase (AMPK), leading to the inhibition of acetyl-CoA carboxylase1 (ACC1) enzyme activity and lipid synthesis. The recuse of the effects of Alox12 depletion using Alox12 metabolites 12S-HETE further confirmed that AMPK and its subsequent inhibition of ACC1 activity and lipid synthesis were the downstream signaling of Alox12 inhibition. Our findings highlighted the important role of Alox12 in breast cancer, particularly in response to chemotherapy. Our work also demonstrate that inhibiting Alox12 is a possible alternative therapeutic strategy to overcome chemoresistance in breast cancer.

Keywords

12(S)-HETE,AMPK,Alox12,Breast cancer,Chemoresistance,Lipid synthesis,

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