Sirtuin-3 (SIRT3), A Novel Potential Therapeutic Target for Head and NeckCancer.

[摘要] Head and neck cancer is the eighth most common cancer worldwide, and squamous cell carcinoma represents the majority of the head and neck cancer cases. Despite the advancements in therapeutic approaches and treatments, the 5-year survival rate of head and neck squamous cell carcinoma (HNSCC) averages 50%. This underscores the urgent need to explore new areas of research and develop new therapeutic drugs that can help improve the survival rate of head and neck cancer patients.Sirtuins (SIRT1–7) have emerged as critical modulators of different tumorigenic processes. However, their role in head and neck cancer has not yet been investigated. We show a novel role for sirtuins, and specifically, SIRT3, in HNSCC tumorigenesis. We found that of all the sirtuins, SIRT3 was overexpressed in oral SCC in vitro and in vivo. SIRT3 downregulation inhibited OSCC cell growth and proliferation, increased its sensitivity to radiation and cisplatin treatments in vitro, and reduced tumor burden in vivo. We also found a link between SIRT3 and anoikis, apoptotic cell death triggered by loss of extracellular matrix contacts. SIRT3 and receptor interacting protein (RIP) are oppositely expressed in OSCC, and OSCC cells escaped anoikis by forming multicellular aggregates or oraspheres to maintain their survival compared to single cells, which underwent anoikis-mediated cell death. Moreover, anoikis-resistant OSCC cells that possess higher SIRT3 and lower RIP expression induced an increase tumor burden and incidence in mice. We also investigated the effect of a novel SIRT3 inhibitor, LC-0296, on HNSCC cells. Interestingly, LC-0296, showed specificity toward retarding HNSCC cell survival and enhancing apoptosis without affecting normal human oral keratinocytes. Additionally, LC-0296 not only worked as a single agent on HNSCC cells, but also synergistically when combined with either radiation or cisplatin treatments. This inhibitory effect was, at least in part, mediated by modulation of ROS levels.In summary, this dissertation work highlights a novel role for sirtuins, and specifically, SIRT3 in HNSCC tumorigenesis. Our data suggest that the development of new therapies targeting specifically SIRT3, may have a promising role in the treatment of HNSCC, and hopefully improve the survival rate of head and neck cancer patients.

[发布机构] University of Michigan

[效力级别] Oral Cancer

[关键词] Head and Neck Cancer;Oral Cancer;Sirtuins;SIRT3;Sirtuin-3;Anoikis;Molecular;Cellular and Developmental Biology;Science;Oral Health Sciences