title: SIRT1-Activating Compounds (STAC) Negatively Regulate Pancreatic Cancer Cell Growth and Viability Through a SIRT1 Lysosomal-Dependent Pathway.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Laboratory of Signal Transduction, Kogod Center on Aging, Mayo Clinic Cancer Center, Rochester, Minnesota. Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, Minnesota.
authors.forename: Claudia C S
authors.initials: CC
authors.lastname: Chini
authors.affiliation: 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.
authors.forename: Jair M
authors.initials: JM
authors.lastname: Espindola-Netto
authors.affiliation: Laboratory of Signal Transduction, Kogod Center on Aging, Mayo Clinic Cancer Center, Rochester, Minnesota. Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, Minnesota.
authors.forename: Gourish
authors.initials: G
authors.lastname: Mondal
authors.affiliation: Laboratory of Signal Transduction, Kogod Center on Aging, Mayo Clinic Cancer Center, Rochester, Minnesota. Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, Minnesota.
authors.forename: Anatilde M Gonzalez
authors.initials: AM
authors.lastname: Guerrico
authors.affiliation: Laboratory of Signal Transduction, Kogod Center on Aging, Mayo Clinic Cancer Center, Rochester, Minnesota. Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, Minnesota.
authors.forename: Veronica
authors.initials: V
authors.lastname: Nin
authors.affiliation: Laboratory of Signal Transduction, Kogod Center on Aging, Mayo Clinic Cancer Center, Rochester, Minnesota. Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, Minnesota.
authors.forename: Carlos
authors.initials: C
authors.lastname: Escande
authors.affiliation: 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.
authors.forename: Mauro
authors.initials: M
authors.lastname: Sola-Penna
authors.affiliation: Department of Biochemistry and Molecular Biology, Division of Oncology Research, Mayo Clinic College of Medicine, Rochester, Minnesota.
authors.forename: Jin-San
authors.initials: JS
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, Division of Oncology Research, Mayo Clinic College of Medicine, Rochester, Minnesota.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Billadeau
authors.affiliation: 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.
authors.forename: Eduardo N
authors.initials: EN
authors.lastname: Chini
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects*; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D006801:Humans; D008247:Lysosomes / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D017239:Paclitaxel / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D056564:Sirtuin 1 / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology; D000093542:Gemcitabine
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; D006576:Heterocyclic Compounds, 4 or More Rings; C525424:SRT1460; C525422:SRT1720; C000601293:SRT3025; D013844:Thiazoles; D003841:Deoxycytidine; D056564:Sirtuin 1; D017239:Paclitaxel; D000093542:Gemcitabine