MMP11 and MMP14 contribute to the interaction between castration-resistant prostate cancer and adipocytes

作者全名："Tan, Bing; Zheng, Xiaoyu; Xie, Xiaoqin; Chen, Yirong; Li, Yuehua; He, Weiyang"

作者地址："[Tan, Bing; Chen, Yirong; Li, Yuehua] Chongqing Med Univ, Univ Town Hosp, Dept Urol, Chongqing 401331, Peoples R China; [Tan, Bing] Chongqing Med Univ, Univ Town Hosp, Med Sci Res Ctr, Chongqing 401331, Peoples R China; [Tan, Bing; He, Weiyang] Chongqing Med Univ, Affiliated Hosp 1, Dept Urol, Chongqing 400016, Peoples R China; [Zheng, Xiaoyu] Chongqing Med & Pharmaceut Coll, Sch Clin Med, Chongqing 401331, Peoples R China; [Xie, Xiaoqin] Chongqing Blood Ctr, Dept Clin Lab, Chongqing 400015, Peoples R China; [He, Weiyang] Chongqing Med Univ, Affiliated Hosp 1, Dept Urol, 1 Youyi Rd, Chongqing 400016, Peoples R China"

通信作者："He, WY (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Dept Urol, 1 Youyi Rd, Chongqing 400016, Peoples R China."

来源：AMERICAN JOURNAL OF CANCER RESEARCH

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001135869900026

JCR分区：Q2

影响因子：5.3

年份：2023

卷号：13

期号：12

开始页：　

结束页：　

文献类型：Article

关键词：Castration resistant prostate cancer; adipocyte; matrix metalloproteinase; mitophagy; lipid metabolism

摘要："Previous studies have demonstrated that adipocytes promote prostate cancer (PCa) cell progression, which facilitates the development of PCa into castration-resistant prostate cancer (CRPC); however, the underlying mechanisms are still not fully understood. Matrix metalloproteinases (MMPs) are a group of proteases responsible for the degradation of extracellular matrix (ECM) and the activation of latent factors. In our study, we detected that MMP11 expression was increased in PCa patients and that a high level of MMP11 was correlated with poor prognosis. Furthermore, siRNA knockdown of MMP11 in CRPC cells not only blocked the delipidation and dedifferentiation of mature adipocytes but also reduced the lipid uptake and utilization of CRPC cells in a cell co-culture model. The number of mitophagosomes and the expression level of Parkin were increased in MMP11-silenced CRPC cells. Moreover, we found that simultaneous downregulation of MMP14 and MMP11 expression may benefit patient survival. Indeed, MMP11/14 knockdown in CRPC cells significantly decreased lipid metabolism and cell invasion, at least partly through the mTOR/HIF1 alpha/MMP2 signaling pathway. Importantly, MMP11/14 knockdown dramatically delayed tumor growth in a xenograft mouse model. Consistently, the decreased lipid metabolism, Ki67 and MMP2 expression, as well as the increased Parkin level were also confirmed in in vivo experiments, further demonstrating the mechanisms responsible for the tumor-promoting effects of MMP11/14. Collectively, our study elucidated the role of MMP11 and MMP14 in the bidirectional crosstalk between adipocytes and CRPC cells and provided the rationale of targeting MMP11/14 for the treatment of CRPC patients."

基金机构："China Post-doctoral Science Foundation [2022MD723740]; Natural Science Foundation of Chongqing, China [cstc2021jcyj-msxmX0704]"

基金资助正文："This study is supported by the China Post-doctoral Science Foundation (Grant Number: 2022MD723740) and the Natural Science Foundation of Chongqing, China (Grant Number: cstc2021jcyj-msxmX0704) ."