2. Academic Validation
  3. SIRT1-Activating Compounds (STAC) Negatively Regulate Pancreatic Cancer Cell Growth and Viability Through a SIRT1 Lysosomal-Dependent Pathway

SIRT1-Activating Compounds (STAC) Negatively Regulate Pancreatic Cancer Cell Growth and Viability Through a SIRT1 Lysosomal-Dependent Pathway

  • Clin Cancer Res. 2016 May 15;22(10):2496-507. doi: 10.1158/1078-0432.CCR-15-1760.
Claudia C S Chini 1,  Jair M Espindola-Netto 2,  Gourish Mondal 1,  Anatilde M Gonzalez Guerrico 1,  Veronica Nin 1,  Carlos Escande 1,  Mauro Sola-Penna 3,  Jin-San Zhang 4,  Daniel D Billadeau 4,  Eduardo N Chini 5
Affiliations

Affiliations

  • 1 Laboratory of Signal Transduction, Kogod Center on Aging, Mayo Clinic Cancer Center, Rochester, Minnesota. Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, Minnesota.
  • 2 Laboratory of Signal Transduction, Kogod Center on Aging, Mayo Clinic Cancer Center, Rochester, Minnesota. Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, Minnesota. Laboratório de Enzimologia e Controle do Metabolismo (LabECoM), Departamento de Biotecnologia Farmacêutica (BioTecFar), Faculdade de Farmácia, Centro de Ciencias da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
  • 3 Laboratório de Enzimologia e Controle do Metabolismo (LabECoM), Departamento de Biotecnologia Farmacêutica (BioTecFar), Faculdade de Farmácia, Centro de Ciencias da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
  • 4 Department of Biochemistry and Molecular Biology, Division of Oncology Research, Mayo Clinic College of Medicine, Rochester, Minnesota.
  • 5 Laboratory of Signal Transduction, Kogod Center on Aging, Mayo Clinic Cancer Center, Rochester, Minnesota. Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, Minnesota. chini.eduardo@mayo.edu.
PMID: 26655844 DOI: 10.1158/1078-0432.CCR-15-1760
Abstract

Purpose: Recent studies suggest that SIRT1-activating compounds (STAC) are a promising class of Anticancer drugs, although their mechanism of action remains elusive. The main goal of this study is to determine the role of STACs as a potential therapy for pancreatic Cancer. In addition, we also explored the mechanism by which these compounds affect pancreatic Cancer.

Experimental design: Using in vitro (Cell Culture experiments) and in vivo (xenograft experiments) approaches, we studied the role of SIRT1 agonists (STAC) in human pancreatic Cancer cell viability and growth.

Results: We show that SIRT1 is highly expressed in pancreatic Cancer cells and that the STACs SRT1720, SRT1460, and SRT3025 inhibited cell growth and survival of pancreatic Cancer cells. STACs enhanced the sensitivity of pancreatic cells to gemcitabine and paclitaxel, indicating that these drugs could be used in combination with other chemotherapy drugs. We also show that STACs were very effective in inhibiting tumor xenograft growth. In mechanistic studies, we observed that STACs activated a SIRT1 lysosomal-dependent cell death. Furthermore, the effect of STACs on cell viability was also dependent on the expression of the endogenous SIRT1 Inhibitor DBC1.

Conclusions: Taken together, our results reveal an essential role for SIRT1 and lysosomes in the death pathway regulated by STACs in pancreatic Cancer cells. Clin Cancer Res; 22(10); 2496-507. ©2015 AACR.

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Products
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  • HY-124037
    98.16%, Sirtuin Activator