FOXM1 contributes to docetaxel resistance in castration-resistant prostate cancer by inducing AMPK/mTOR-mediated autophagy.

Docetaxel-mediated chemotherapy is the first line therapy for metastatic castration-resistant prostate cancer (CRPC) patients, but its therapeutic benefit is limited by the development of resistance. Although Forkhead box protein M1 (FOXM1) has been implicated in prostate tumorigenesis and metastasis, its role in docetaxel resistance has not been studied. Here, we showed that FOXM1 expression was upregulated in the docetaxel resistant CRPC cell lines (PC3-DR and VCaP-DR) and knockdown of FOXM1 sensitized the cells to docetaxel both in vitro and in vivo. In addition, autophagy was found to be significantly enhanced in resistant cells. Moreover, FOXM1 overexpression cells showed increased autophagic flux and higher numbers of autophagosomes. Knockdown of ATG7, beclin-1 or cotreatment with chloroquine, partly restored sensitivity to docetaxel in the FOXM1-overexpressing cells. Mechanistically, FOXM1 targeted AMPK/mTOR to activate the autophagy pathway and altered docetaxel response in CRPC. These findings identify the role of FOXM1 as well as the mechanism underlying FOXM1 action in docetaxel sensitivity and may, therefore, aid in design of CRPC therapies.

Cancer letters. 2019 Nov 15 [Epub ahead of print]

Jian-Zhong Lin, Wei-Wan Wang, Ting-Ting Hu, Gang-Yi Zhu, Li-Nan Li, Cheng-Yang Zhang, Zheng Xu, Hong-Bo Yu, Hong-Fei Wu, Jia-Geng Zhu

Department of Urology, BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, 210019, China. Electronic address: ., Department of Central Laboratory, BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, 210019, China., Department of Oncology, The First Clinical Medical College, Nanjing Medical University, Nanjing, 210009, China., Department of Oncology, Academy of Pediatrics, Nanjing Medical University, Nanjing, 210009, China., Department of Urology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, 210006, China., Department of Urology, BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, 210019, China., Department of Urology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, 210006, China. Electronic address: .