Membrane metallo-endopeptidase mediates cellular senescence induced by oncogenic PIK3CA(H1047R) accompanied with pro-tumorigenic secretome

doi:10.1002/ijc.32153

	Membrane metallo-endopeptidase mediates cellular senescence induced by oncogenic PIK3CA(H1047R) accompanied with pro-tumorigenic secretome
	Liu, Xue-Ling 1,2; Liu, Jia-Li 1; Xu, Yi-Chao 1; Zhang, Xi 1; Wang, Yu-Xiang 1; Qing, Li-Hua 1; Guo, Wei 1; Ding, Jian 1,2; Meng, Ling-Hua 1,2
刊名	INTERNATIONAL JOURNAL OF CANCER
	2019-08-01
卷号	145 期号:3 页码:817-829
关键词	PI3K alpha membrane metallo-endopeptidase senescence macrophage breast cancer
ISSN号	0020-7136
DOI	10.1002/ijc.32153
通讯作者	Ding, Jian(jding@simm.ac.cn) ; Meng, Ling-Hua(lhmeng@simm.ac.cn)
英文摘要	The hotspot mutation H1047R in the oncogenic PIK3CA gene is frequently detected in breast cancer and enhances the enzymatic activity of PI3K to activate AKT/mTOR signaling cascade. Aberrant elevated PI3K activation has been reported to promote the tumorigenesis of breast cancer, but the mechanisms underlying are still needed to be elucidated. Here, we found that continuously activating PIK3CA(H1047R) conferred human mammary epithelial MCF-10A cells to cellular senescence upon serum-starvation. Similarly, breast cancer T47D and HCC1954 cells harboring H1047R mutation were senescent when cells were deprived of serum. PI3K/AKT/mTOR axis but not p53 or RB might be required for the induction of senescence. Notably, membrane metallo-endopeptidase (MME) was identified as a downstream effector of PI3K to mediate the induction of senescence, which might be associated with its glycosylation. Senescent cells elicited a distinct secretome dependent on PI3K and MME. Specifically, IL-6 promoted the proliferation of normal cells and CCL2 induced the M2-like polarization of macrophages, which might create an immunosuppressive microenvironment during the initiation and/or development of breast cancer. This study shed new light on the tumorigenesis induced by hyper-activated PI3K and might provide new clues for the prevention and therapy of breast cancer.
资助项目	Personalized Medicines-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences, Chinese Academy of Sciences[XDA12020218] ; Personalized Medicines-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences, Chinese Academy of Sciences[XDA12020111] ; National Science and Technology Major Project Key New Drug Creation and Manufacturing Program, Ministry of Science and Technology of the People's Republic of China[2018ZX09711002-011] ; Fudan-SIMM Joint Research Fund ; National Natural Science Foundation of China[81773760]
WOS关键词	NEUTRAL ENDOPEPTIDASE ; COMPREHENSIVE ANALYSIS ; PROTEIN GLYCOSYLATION ; PIK3CA MUTATIONS ; CD10 EXPRESSION ; MOUSE MODELS ; INHIBITOR ; PI3K ; NEPRILYSIN ; DEFICIENT
WOS研究方向	Oncology
语种	英语
出版者	WILEY
WOS记录号	WOS:000470911700024
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/289664]
专题	中国科学院上海药物研究所
通讯作者	Ding, Jian; Meng, Ling-Hua
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, Beijing, Peoples R China
推荐引用方式 GB/T 7714	Liu, Xue-Ling,Liu, Jia-Li,Xu, Yi-Chao,et al. Membrane metallo-endopeptidase mediates cellular senescence induced by oncogenic PIK3CA(H1047R) accompanied with pro-tumorigenic secretome[J]. INTERNATIONAL JOURNAL OF CANCER,2019,145(3):817-829.
APA	Liu, Xue-Ling.,Liu, Jia-Li.,Xu, Yi-Chao.,Zhang, Xi.,Wang, Yu-Xiang.,...&Meng, Ling-Hua.(2019).Membrane metallo-endopeptidase mediates cellular senescence induced by oncogenic PIK3CA(H1047R) accompanied with pro-tumorigenic secretome.INTERNATIONAL JOURNAL OF CANCER,145(3),817-829.
MLA	Liu, Xue-Ling,et al."Membrane metallo-endopeptidase mediates cellular senescence induced by oncogenic PIK3CA(H1047R) accompanied with pro-tumorigenic secretome".INTERNATIONAL JOURNAL OF CANCER 145.3(2019):817-829.