Abstract
The FDA-approved anti-androgen Enzalutamide (Enz) has been used successfully as the last line therapy to extend castration-resistant prostate cancer (CRPC) patients’ survival by an extra 4.8 months. However, CRPC patients eventually develop Enz-resistance that may involve the induction of the androgen receptor (AR) splicing variant ARv7. Here we found that Cisplatin (Cis) or Carboplatin, currently used in chemotherapy/radiation therapy to suppress tumor progression, could restore the Enz sensitivity in multiple Enz-resistant (EnzR) CRPC cells via directly degrading/suppressing the ARv7. Combining Cis or Carboplatin with Enz therapy can also delay the development of Enz-resistance in CRPC C4-2 cells. Mechanism dissection found that Cis or Carboplatin might decrease the ARv7 expression via multiple mechanisms including targeting the lncRNA-Malat1/SF2 RNA splicing complex and increasing ARv7 degradation via altering ubiquitination. Preclinical studies using in vivo mouse model with implanted EnzR1-C4-2 cells also demonstrated that Cis plus Enz therapy resulted in better suppression of EnzR CRPC progression than Enz treatment alone. These results not only unveil the previously unrecognized Cis mechanism to degrade ARv7 via targeting the Malat1/SF2 complex and ubiquitination signals, it may also provide a novel and ready therapy to further suppress the EnzR CRPC progression in the near future.
Highlights
Prostate cancer (PCa) is the second leading cause of death among men in the United States[1]
Clinical studies indicated the failure of ADT with Enz (ADT-Enz) treatment might be linked to the androgen receptor (AR) splicing variant ARv78,9, a process that involves the splicing of full-length AR pre-mRNA9,10 and altering the RNA splicing pattern[11]
We found similar results when we replaced the Cis with carboplatin showing low dose of carboplatin plus Enz could suppress EnzR1_C4-2 growth (Fig. 2g–i)
Summary
Prostate cancer (PCa) is the second leading cause of death among men in the United States[1]. It is estimated that there will be 191,930 new cases of PCa and 33,330 associated deaths worldwide in 20202. Enzalutamide (Enz) could suppress the castration resistant PCa (CRPC) and might extend patients overall survival by 4.8 months[7]. Patients still eventually develop Enz-resistance[8]. Clinical studies indicated the failure of ADT with Enz (ADT-Enz) treatment might be linked to the AR splicing variant ARv78,9, a process that involves the splicing of full-length AR pre-mRNA9,10 and altering the RNA splicing pattern[11]. While other mechanistic studies indicated that the development
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