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 β-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.

中文翻译：

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SIRT1 抑制诱导衰老作为预防前列腺癌进展的策略

新的证据表明 SIRT1（一种烟酰胺腺嘌呤二核苷酸 (NAD) 依赖性脱乙酰酶）在癌症发生、进展和治疗耐药中发挥着重要作用；使其成为可行的治疗靶点。在这里，我们研究了白藜芦醇介导的 SIRT1 药理激活对 HGPIN 病变进展（使用 Pten − ^/−小鼠模型）和前列腺肿瘤发展（使用SIRT1稳定沉默的前列腺癌细胞原位模型）的影响。我们证明精确的 SIRT1 调节可以有益于癌症的预防和治疗。SIRT1 激活的积极作用可以预防Pten如果早期（癌前阶段）给予白藜芦醇，则小鼠中HGPIN损伤的缺失驱动发展在HGPIN损伤建立或肿瘤细胞植入后几乎没有任何益处。从机制上讲，我们的结果表明，在雄激素剥夺条件下，SIRT1 抑制会诱导衰老，与衰老负调节因子相关的基因特征减少和衰老相关 β-半乳糖苷酶活性增加就证明了这一点。此外，SIRT1 的药理学抑制增强了临床雄激素受体阻断剂和放射的生长抑制作用。总而言之，我们的研究结果为 SIRT1 在前列腺肿瘤发生中的作用的差异提供了解释。我们的结果表明，SIRT1 的双重作用可能以阶段和环境依赖性方式发生，通过发挥抗肿瘤作用来预防早期前列腺病变发展，同时促进肿瘤发展和病变后疾病进展。在临床上，这些数据强调了精确 SIRT1 调节对于为癌症预防和治疗提供益处（包括提高对传统治疗方法的敏感性）的重要性。