The PIK3CA-E545K-SIRT4 signaling axis reduces radiosensitivity by promoting glutamine metabolism in cervical cancer. (1st March 2023)

• Record Type: Journal Article
• Authors: Jiang, Wei; Ouyang, Xueyan; Ji, Zhaodong; Shi, Wanling; Wu, Yutuan; Yao, Qianlan; Wang, Yi; Yang, Wentao; Xiang, Libing; Yang, Huijuan
• Is Part Of: Cancer letters. Volume 556(2023)
• Publication Date: 2023-03-01
• Subjects: PIK3CA-E545K mutation -- Glutamine metabolism -- SIRT4 -- GPT1 -- Radiosensitivity -- Cervical cancer; IR irradiation -- GLS glutaminase -- GOT1 glutamate oxaloacetate, transaminase -- ATP adenosine triphosphate -- WT wild type -- ROS reactive oxygen species -- CCK-8 cell counting kit-8 -- TCGA the Cancer Genome Atlas -- EVE everolimus -- mTOR mammalian target of rapamycin -- CREB cAMP-response element binding protein; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2023.216064
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: The mutation of glutamic acid 545 to lysine (E545K) in PIK3CA, as the most common missense mutation of this gene in various cancer types, is frequently observed in cervical cancer and has been shown to reduce cervical cancer radiosensitivity. However, the underlying mechanisms remain unclear. Here, we implicate the alterations of glutamine metabolism in PIK3CA -E545K-mediated radioresistance of cervical cancer. Specifically, PIK3CA mutation negatively regulated the expression of SIRT4 via the epigenetic regulator EP300 independently of the canonical mTORC1 pathway. PIK3CA -E545K-induced SIRT4 downregulation promoted cell proliferation, migration, and radiation-induced DNA repair and apoptosis, while SIRT4 overexpression reversed the radioresistance phenotype mediated by PIK3CA mutation. Mechanistically, SIRT4 modulated glutamine metabolism and thus cellular apoptosis by negatively regulating a glutamate pyruvate transaminase GPT1. Moreover, the PI3K inhibitor BYL719, but not mTOR inhibitors, exerted remarkable synergistic effects with radiotherapy by inhibiting glutamine metabolism in vitro and in vivo. Collectively, this study reveals the role of PIK3CA -E545K-SIRT4 axis in regulating glutamine metabolism and the radioresistance in cervical cancer, which provides a necessary preliminary basis for clinical research of PI3K inhibitors as radiosensitizing agents.