The antiproliferative and apoptotic effects of sirtinol, a sirtuin inhibitor on human lung cancer cells by modulating Akt/β-catenin-Foxo3a axis.

Abstract

Sirtuins, NAD(+)-dependent deacetylases, could target both histones and nonhistone proteins in mammalian cells. Sirt1 is the major sirtuin and has been shown to involve various cellular processes, including antiapoptosis, cellular senescence. Sirt1 was reported to be overexpressed in many cancers, including lung cancer. Sirtinol, a specific inhibitor of Sirt1, has been shown to induce apoptosis of cancer cells by elevating endogenous level of reactive oxygen species. In the study, we investigated the effect of sirtinol on the proliferation and apoptosis of nonsmall cell lung cancer (NSCLC) H1299 cells. The results of proliferation assay and colony formation assay showed the antigrowth effect of sirtinol. The annexin-V staining further confirmed the apoptosis induction by sirtinol treatment. Interestingly, the levels of phosphorylated Akt and β-catenin were significantly downregulated with treating the apoptotic inducing doses. On the contrary, sirtinol treatment causes the significantly increased level of FoxO3a, a proapoptotic transcription factor targeted by Sirt1. These above results suggested that sirtinol may inhibit cell proliferation of H1299 cells by regulating the axis of Akt-β-catenin-FoxO3a. Overall, this study demonstrates that sirtinol attenuates the proliferation and induces apoptosis of NSCLC cells, indicating the potential treatment against NSCLC cells by inhibiting Sirt1 in future applications.

• Authors: Yao Fong, Yin-Chieh Lin, Chang-Yi Wu, Hui-Min David Wang, Li-Li Lin, Han Lin Chou, Yen-Ni Teng, Shyng-Shiou Yuan, Chien-Chih Chiu
• Journal: TheScientificWorldJournal (ScientificWorldJournal) Vol. 2014 Pg. 937051 ( 2014) ISSN: 1537-744X [Electronic] United States
• PMID: 25184156 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Benzamides
• FOXO3 protein, human
• Forkhead Box Protein O3
• Forkhead Transcription Factors
• Naphthols
• beta Catenin
• sirtinol
• Proto-Oncogene Proteins c-akt

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Benzamides (pharmacology)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Forkhead Box Protein O3
• Forkhead Transcription Factors (metabolism)
• Gene Expression
• Humans
• Lung Neoplasms (genetics, metabolism)
• Models, Biological
• Naphthols (pharmacology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction (drug effects)
• Tumor Stem Cell Assay
• beta Catenin (metabolism)