SIRT1 inhibition-induced senescence as a strategy to prevent prostate cancer progression

Emerging evidence suggests an important role for SIRT1, a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase in cancer development, progression and therapeutic resistance; making it a viable therapeutic target. Here, we examined the impact of resveratrol-mediated pharmacological activation of SIRT1 on the progression of HGPIN lesions (using the Pten(-/-) mouse model) and on prostate tumor development (using an orthotopic model of prostate cancer cells stably silenced for SIRT1). We show that precise SIRT1 modulation could benefit both cancer prevention and treatment. Positive effect of SIRT1 activation can prevent Pten deletion-driven development of HGPIN lesions in mice if resveratrol is administered early (pre-cancer stage) with little to no benefit after the establishment of HGPIN lesions or tumor cell implantation. Mechanistically, our results show that under androgen deprivation conditions, SIRT1 inhibition induces senescence as evidenced by decreased gene signature associated with negative regulators of senescence and increased senescence-associated beta-galactosidase activity. Furthermore, pharmacological inhibition of SIRT1 potentiated growth inhibitory effects of clinical androgen receptor blockade agents and radiation. Taken together, our findings provide an explanation for the discrepancy regarding the role of SIRT1 in prostate tumorigenesis. Our results reveal that the bifurcated roles for SIRT1 may occur in stage and context-dependent fashion by functioning in an antitumor role in prevention of early-stage prostate lesion development while promoting tumor development and disease progression post-lesion development. Clinically, these data highlight the importance of precise SIRT1 modulation to provide benefits for cancer prevention and treatment including sensitization to conventional therapeutic approaches.

Automated summary

Emerging evidence suggests that SIRT1 plays an important role in cancer development, progression, and therapeutic resistance, making it a potential therapeutic target. This study investigated the impact of resveratrol-mediated activation of SIRT1 on the progression of HGPIN lesions and prostate tumor development. The results showed that precise modulation of SIRT1 can benefit both cancer prevention and treatment. Activation of SIRT1 with resveratrol can prevent the development of HGPIN lesions in mice if administered early, but has little to no effect after the establishment of lesions or tumor cell implantation. Mechanistically, SIRT1 inhibition induces senescence under androgen deprivation conditions, and pharmacological inhibition of SIRT1 enhances the effects of clinical androgen receptor blockade agents and radiation. These findings provide an explanation for the contradictory role of SIRT1 in prostate tumorigenesis, highlighting the importance of precise SIRT1 modulation for cancer prevention and treatment.