TPD52 (isoform 3) promotes resistance to mTOR-targeted inhibitors by regulating c-Myc, PTEN, and direct activation of 4E-BP1 in LNCaP androgen-dependent cells.

A therapeutic strategy targeting the PI3K-AKT-mTOR pathway is widely seen as promising against prostate cancer (PCa) treatment. However, resistance to targeted inhibitors is still a major challenge. Herein we observed that the overexpression of TPD52 (isoform 3) in LNCaP, PCa cells confers resistance to mTOR inhibitors, specifically everolimus and rapamycin. This study demonstrates that TPD52 promotes the proliferation and survival of tumor cells treated with mTOR inhibitors by hyperactivating PI3K/AKT. Despite the inactivation of downstream targets like p70S6K and S6 upon mTOR inhibition, p4E-BP1 remained consistently high in TPD52 overexpressing LNCaP cells, suggesting activation of an alternative regulatory mechanism independent of mTOR. Furthermore, elevated c-Myc levels were correlated with overexpression of TPD52 and were linked to loss of PTEN expression further promoting drug resistance. Contrarily, silencing of TPD52 and c-Myc sensitized LNCaP cells to mTOR inhibitors by restoring PTEN levels and further downregulation of 4E-BP1. Above all, downregulation of both TPD52 and c-Myc enhanced the sensitivity of LNCaP-TPD52 cells facilitating apoptosis indicating a potential strategy to overcome resistance to mTOR inhibitors in PCa. Taken together, these findings underscore the role of TPD52 through c-Myc in conferring resistance to mTOR inhibitors and warrant further exploration of their molecular mechanisms in PCa treatment.