Chini Claudia C S, Espindola-Netto Jair M, Mondal Gourish, Guerrico Anatilde M Gonzalez, Nin Veronica, Escande Carlos, Sola-Penna Mauro, Zhang Jin-San, Billadeau Daniel D, Chini Eduardo N
Laboratory of Signal Transduction, Kogod Center on Aging, Mayo Clinic Cancer Center, Rochester, Minnesota. Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, Minnesota.
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.
Clin Cancer Res. 2016 May 15;22(10):2496-507. doi: 10.1158/1078-0432.CCR-15-1760. Epub 2015 Dec 11.
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.
近期研究表明，SIRT1激活化合物（STAC）是一类很有前景的抗癌药物，尽管其作用机制仍不清楚。本研究的主要目的是确定STAC作为胰腺癌潜在治疗方法的作用。此外，我们还探讨了这些化合物影响胰腺癌的机制。
我们采用体外（细胞培养实验）和体内（异种移植实验）方法，研究了SIRT1激动剂（STAC）在人胰腺癌细胞活力和生长中的作用。
我们发现SIRT1在胰腺癌细胞中高表达，并且STAC类药物SRT1720、SRT1460和SRT3025可抑制胰腺癌细胞的生长和存活。STAC增强了胰腺细胞对吉西他滨和紫杉醇的敏感性，表明这些药物可与其他化疗药物联合使用。我们还发现STAC在抑制肿瘤异种移植生长方面非常有效。在机制研究中，我们观察到STAC激活了一种依赖SIRT1溶酶体的细胞死亡。此外，STAC对细胞活力的影响还取决于内源性SIRT1抑制剂DBC1的表达。
综上所述，我们的结果揭示了SIRT1和溶酶体在STAC调控的胰腺癌细胞死亡途径中的重要作用。《临床癌症研究》；22(10)；2496 - 507。©2015美国癌症研究协会。
