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

Autor: Huang SB; Department of Molecular Medicine, The University of Texas Health at San Antonio, San Antonio, Texas, USA., Rivas P; Department of Molecular Medicine, The University of Texas Health at San Antonio, San Antonio, Texas, USA., Yang X; Department of Molecular Medicine, The University of Texas Health at San Antonio, San Antonio, Texas, USA., Lai Z; Department of Epidemiology and Biostatistics, UT Health at San Antonio Greehey Children's Cancer Research Institute, San Antonio, Texas, USA., Chen Y; Department of Epidemiology and Biostatistics, UT Health at San Antonio Greehey Children's Cancer Research Institute, San Antonio, Texas, USA., Schadler KL; Department of Pediatrics, MD Anderson Cancer Center, Houston, Texas, USA., Hu M; College of Pharmacy, University of Houston, Houston, Texas, USA., Reddick RL; Department of Pathology, The University of Texas Health at San Antonio, San Antonio, Texas, USA., Ghosh R; Department of Molecular Medicine, The University of Texas Health at San Antonio, San Antonio, Texas, USA.; Department of Urology, The University of Texas Health at San Antonio, San Antonio, Texas, USA.; Mays Cancer Center, The University of Texas Health San Antonio MD Anderson, San Antonio, Texas, USA., Kumar AP; Department of Molecular Medicine, The University of Texas Health at San Antonio, San Antonio, Texas, USA.; Department of Urology, The University of Texas Health at San Antonio, San Antonio, Texas, USA.; Mays Cancer Center, The University of Texas Health San Antonio MD Anderson, San Antonio, Texas, USA.; South Texas Veterans Health Care System, San Antonio, Texas, USA.
Jazyk: angličtina
Zdroj: Molecular carcinogenesis [Mol Carcinog] 2022 Jul; Vol. 61 (7), pp. 702-716. Date of Electronic Publication: 2022 Apr 22.
DOI: 10.1002/mc.23412
Abstrakt: 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.
(© 2022 Wiley Periodicals LLC.)
Databáze: MEDLINE
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