RGCC-mediated PLK1 activity drives breast cancer lung metastasis by phosphorylating AMPKα2 to activate oxidative phosphorylation and fatty acid oxidation

作者全名："Cheng, Shaojie; Wan, Xueying; Yang, Liping; Qin, Yilu; Chen, Shanchun; Liu, Yongcan; Sun, Yan; Qiu, Yuxiang; Huang, Luyi; Qin, Qizhong; Cui, Xiaojiang; Wu, Mingjun; Liu, Manran"

作者地址："[Cheng, Shaojie; Wan, Xueying; Chen, Shanchun; Liu, Yongcan; Qiu, Yuxiang; Liu, Manran] Chongqing Med Univ, Key Lab Lab Med Diagnost, Chinese Minist Educ, 1 Yi Xue Yuan Rd, Chongqing 400016, Peoples R China; [Yang, Liping] Chongqing Med Univ, Affiliated Hosp 2, Dept Lab Med, Chongqing 400010, Peoples R China; [Qin, Yilu] Chongqing Hosp Tradit Chinese Med, Chongqing Key Lab Sichuan Chongqing Coconstruct Di, Chongqing 400021, Peoples R China; [Sun, Yan] Chongqing Med Univ, Basic Med Sch, Dept Cell Biol & Med Genet, Chongqing 400016, Peoples R China; [Huang, Luyi] Chongqing Med Univ, Key Lab Mol Biol Infect Dis Designated, Chinese Minist Educ, Chongqing 400016, Peoples R China; [Qin, Qizhong] Chongqing Med Univ, Expt Teaching Ctr Basic Med Sci, Chongqing 400016, Peoples R China; [Cui, Xiaojiang] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Dept Surg, Dept Obstet & Gynecol, Los Angeles, CA 91006 USA; [Wu, Mingjun] Chongqing Med Univ, Inst Life Sci, 1 Yi Xue Yuan Rd, Chongqing 400016, Peoples R China"

通信作者："Liu, MR (通讯作者)，Chongqing Med Univ, Key Lab Lab Med Diagnost, Chinese Minist Educ, 1 Yi Xue Yuan Rd, Chongqing 400016, Peoples R China.; Wu, MJ (通讯作者)，Chongqing Med Univ, Inst Life Sci, 1 Yi Xue Yuan Rd, Chongqing 400016, Peoples R China."

来源：JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001125217400002

JCR分区：Q1

影响因子：11.3

年份：2023

卷号：42

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：RGCC; Lung metastasis; PLK1; OXPHOS; Fatty acid oxidation

摘要："BackgroundMore than 90% of the mortality of triple-negative breast cancer (TNBC) patients is attributed to cancer metastasis with organotropism. The lung is a frequent site of TNBC metastasis. However, the precise molecular mechanism for lung-specific metastasis of TNBC is not well understood.MethodsRNA sequencing was performed to identify patterns of gene expression associated with lung metastatic behavior using 4T1-LM3, MBA-MB-231-LM3, and their parental cells (4T1-P, MBA-MB-231-P). Expressions of RGCC, called regulator of cell cycle or response gene to complement 32 protein, were detected in TNBC cells and tissues by qRT-PCR, western blotting, and immunohistochemistry. Kinase activity assay was performed to evaluate PLK1 kinase activity. The amount of phosphorylated AMP-activated protein kinase alpha 2 (AMPK alpha 2) was detected by immunoblotting. RGCC-mediated metabolism was determined by UHPLC system. Oxidative phosphorylation was evaluated by JC-1 staining and oxygen consumption rate (OCR) assay. Fatty acid oxidation assay was conducted to measure the status of RGCC-mediated fatty acid oxidation. NADPH and ROS levels were detected by well-established assays. The chemical sensitivity of cells was evaluated by CCK8 assay.ResultsRGCC is aberrantly upregulated in pulmonary metastatic cells. High level of RGCC is significantly related with lung metastasis in comparison with other organ metastases. RGCC can effectively promote kinase activity of PLK1, and the activated PLK1 phosphorylates AMPK alpha 2 to facilitate TNBC lung metastasis. Mechanistically, the RGCC/PLK1/AMPK alpha 2 signal axis increases oxidative phosphorylation of mitochondria to generate more energy, and promotes fatty acid oxidation to produce abundant NADPH. These metabolic changes contribute to sustaining redox homeostasis and preventing excessive accumulation of potentially detrimental ROS in metastatic tumor cells, thereby supporting TNBC cell survival and colonization during metastases. Importantly, targeting RGCC in combination with paclitaxel/carboplatin effectively suppresses pulmonary TNBC lung metastasis in a mouse model.ConclusionsRGCC overexpression is significantly associated with lung-specific metastasis of TNBC. RGCC activates AMPK alpha 2 and downstream signaling through RGCC-driven PLK1 activity to facilitate TNBC lung metastasis. The study provides implications for RGCC-driven OXPHOS and fatty acid oxidation as important therapeutic targets for TNBC treatment."

基金机构：National key projects of Ministry of Science and Technology of China

基金资助正文：No Statement Available