Cancer-associated fibroblasts regulate mitochondrial metabolism and inhibit chemosensitivity via ANGPTL4-IQGAP1 axis in prostate cancer

作者：Zhi Xiong, Ruilin Zhuang, Shun-Li Yu, Zhaoxiang Xie, Shirong Peng, Zean Li, Bingheng Li, Junjia Xie, Yining Li, Kaiwen Li, Hai Huang · 发表于：Journal of Advanced Research · 年份：2024 · DOI：10.1016/j.jare.2024.12.003 · 被引用次数：28 · 研究领域：Lipid metabolism and disorders、Angiogenesis and VEGF in Cancer、Kruppel-like factors research

INTRODUCTION: Cancer-associated fibroblasts (CAFs) are a critical component of the tumor microenvironment, being implicated in enhancing tumor growth and fostering drug resistance. Nonetheless, the mechanisms underlying their function in prostate cancer (PCa) remain incompletely understood, which is essential for devising effective therapeutic strategies. OBJECTIVES: The main objective of this study was to explore the mechanisms by which CAFs mediate PCa growth and chemoresistance. METHODS: We validated through data analysis and experimentation that CAFs significantly impact PCa cell proliferation and chemoresistance. Subsequently, we conducted a comprehensive proteomic analysis of the conditioned media from CAFs and PCa cells and identified angiopoietin-like protein 4 (ANGPTL4) as a key factor. We employed ELISA and multiplex immunofluorescence assays, all of which indicated that ANGPTL4 was primarily secreted by CAFs.Next, we conducted metabolomics analysis, GST pull-down assays, Co-IP, and other experiments to explore the specific molecular mechanisms of ANGPTL4 and its precise effects on PCa cells. Through drug screening, we identified Quercetin 3-O-(6'-galactopyranosyl)-β-D-galactopyranoside (QGGP) as an effective inhibitor of CAFs function. Finally, we thoroughly assessed the therapeutic potential of QGGP both as a monotherapy and in combination with docetaxel in PCa cells. RESULTS: We discovered that the extracrine factor ANGPTL4 is primarily expressed in CAFs in PCa. ...