Abstract 5082: SIRT1 functions as a double-edged sword in prostate cancer

Abstract

Abstract SIRT1 is a NAD+ dependent deacetylase known to regulate a plethora of biological processes through posttranslational regulation of proteins including those that function as tumor promoters and suppressors. In order to define the role of SIRT1 in prostate pathogenesis, we used 2 mouse models: (i) PTEN knockout (PTENKO) mouse model by pharmacological activation of SIRT1 with resveratrol (RES) a known activator of SIRT1, & (ii) orthotopic implantation model with genetic silencing of SIRT1 (SIRT1 shRNA). We also used genetic and pharmacologic inhibition of SIRT1 in cell culture models to understand the mechanism. We tested whether SIRT1 modulation is beneficial when targeted early (before the establishment of prostatic lesions) or late (after the establishment of prostatic lesions) in the PTENKO model. RES intervention was initiated in 4-5-week (early intervention) and 10-15-week-old (late intervention) PTENKO mice. Analyses of samples collected longitudinally during progression revealed that early intervention with RES reduced incidence of high-grade prostate intraepithelial neoplastic lesions (HGPIN) when given for 14 weeks with no significant difference at 7 or at 11 weeks. On the other hand, late intervention after the establishment of HGPIN lesions with RES had no beneficial effect. Importantly, longer treatment duration (28 weeks) resulted in significantly increased incidence of invasive prostate carcinoma. Furthermore, RES had no significant effect on the development of orthotopic prostate tumors following implantation of LNCaP cells in nude mice. In contrast, orthotopic implantation of SIRT1 stably silenced LNCaP cells showed significant impairment in tumor development. Immunohistochemical evaluation showed nuclear localization of SIRT1 in human prostate tumors and was associated with increased risk of biochemical recurrence. Mechanistic investigations revealed (i) suppression of AR signaling in hormone-sensitive LNCaP but not in castration-resistant 22Rv1 cells; (ii) RNAseq coupled with gene ontology enrichment analysis using SIRT1 silenced cells under conditions of androgen stimulation and inhibition identified genes involved in cell cycle checkpoint and senescence as top pathways affected by SIRT1 loss of function. In silicoanalysis shows that the identified SIRT1-regulated targets are associated with disease aggressiveness and poor disease-free survival. Taken together these data demonstrate that (i) SIRT1 plays a contextual role during prostate pathogenesis by functioning as tumor suppressor during early stage and as a tumor promoter during late stage; (ii) SIRT1 inhibition suppresses tumor development and (iii) RES is a better preventive than therapeutic agent. Therefore, our findings offer promising avenues to develop SIRT1-regulated pathways as novel therapeutic targets to inhibit prostate cancer recurrence. Supported by CPRIT Training Grant RP 170345 (SH) and CPRIT RP 150166 (APK) Citation Format: Shih-Bo Huang, Dinesh Thapa, Roble G. Bedolla, Amanda R. Muñoz, Xiaoyu Yang, Paul Rivas, Robert L. Reddick, Hiroshi Miyamoto, Rita Ghosh, Addanki Pratap Kumar. SIRT1 functions as a double-edged sword in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5082.