Inhibiting cytoplasmic accumulation of HuR synergizes genotoxic agents in urothelial carcinoma of the bladder.
HuR, an RNA-binding protein, post-transcriptionally regulates nearly 4% of encoding proteins implicated in cell survival. Here we show that HuR is required for the efficacy of chemotherapies in urothelial carcinoma of the bladder. We identify pyrvinium pamoate, an FDA-approved anthelminthic drug, as a novel HuR inhibitor that dose-dependently inhibited cytoplasmic accumulation of HuR. Combining pyrvinium pamoate with chemotherapeutic agents (e.g. cisplatin, doxorubicin, vincristine and oxaliplatin) not only led to enhanced cytotoxicity in bladder cancer cells but also synergistically suppressed the growth of patient-derived bladder tumor xenografts in mice (P < 0.001). Mechanistically, pyrvinium pamoate promoted nuclear import of HuR by activating the AMP-activated kinase/importin α1 cascade and blocked HuR nucleo-cytoplasmic translocation by inhibiting the checkpoint kinase1/cyclin-dependent kinase 1 pathway. Notably, pyrvinium pamoate-additive treatment increased DNA double-strand breaks as indicated by elevated γH2AX expression, suggesting an involvement of DNA damage response. We further found that pyrvinium pamoate dramatically downregulated several key DNA repair genes in genotoxically-stressed cells, including DNA ligase IV and BRCA2, leading to unbearable genomic instability and cell death. Collectively, our findings are the first to characterize a clinical HuR inhibitor and provide a novel therapeutically tractable strategy by targeting cytoplasmic translocation of HuR for treatment of urothelial carcinoma of the bladder.
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
Jiawei
J
Guo
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
Jing
J
Lv
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
Siyu
S
Chang
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
Zhi
Z
Chen
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
Weiqiang
W
Lu
Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
Chuanliang
C
Xu
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.|Institute of Biosciences and Technology, Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, Houston, Texas 77030, USA.
Mingyao
M
Liu
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
Xiufeng
X
Pang
D055372:AMP-Activated Protein Kinases / Q000502:physiology; D021581:Active Transport, Cell Nucleus; D000818:Animals; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D000067780:ELAV-Like Protein 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D042822:Genomic Instability; D006801:Humans; D051379:Mice; D011774:Pyrvinium Compounds / Q000627:therapeutic use*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D011774:Pyrvinium Compounds; C024631:pyrvinium; D016203:CDC2 Protein Kinase; D055372:AMP-Activated Protein Kinases
DNA damage response; RNA-binding protein; chemosensitivity; pyrvinium pamoate; urothelial carcinoma of the bladder