Inhibiting cytoplasmic accumulation of HuR synergizes genotoxic agents in urothelial carcinoma of the bladder

Abstract

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.

RNA-Binding Protein HuR Regulates Both Mutant and Wild-Type IDH1 in IDH1-Mutated Cancer

“…Existing drugs with anti-HuR properties (e.g., pyrvinium pamoate; ref. 51) or even novel HuR inhibitors (52) should be explored in conjunction with Mut.IDH1 inhibitors. Second, WT.IDH1 likely Figure 7.…”

Targeting the interaction between RNA-binding protein HuR and FOXQ1 suppresses breast cancer invasion and metastasis

“…These small molecules show moderate to high binding affinity to HuR in different biochemical assays and have been validated as HuR inhibitors 23 . However, only a few of them are potently cytotoxic to cancer cells and therapeutic efficacy of HuR inhibitors was only examined in bladder cancer xenograft model 24 and colorectal cancer xenograft models [25][26][27] .…”

HuR/ELAVL1 drives malignant peripheral nerve sheath tumor growth and metastasis

“…We first focused on the YAP/TAZ pathway. In an elegant study, it was recently shown that human MPNSTs exhibit ele-Pharmacological inhibition of HuR with MS-444, which inhibits HuR homodimerization to prevent the binding of 3′-UTR AU-rich elements (29); pyrvinium pamoate, an FDA-approved anthelmintic drug that blocks HuR nucleocytoplasmic translocation (30); and tanshinone mimic 6N (TM-6N), which inhibits HuR-RNA complex formation (31), each strongly reduced MPNST cell growth in culture in ST88-14 and STS-26T cells ( Figure 5, A and B), similarly to what we found through the genetic inhibition of HuR (Supplemental Figures 3 and 4).…”