Omega-3 Polyunsaturated Fatty Acids Induce Apoptotic And Autophagic Cell Death Through Inhibition Of Akt/Mtor Pathway In Human Oral Cancer Cells

Omega-3 polyunsaturated fatty acids (ω3-PUFAs) have been found to possess anticancer properties in a variety of cancer cell lines and animal models, but their effect in oral cancer remains unclear. This study was designed to examine the impact of ω3-PUFAs on oral cancer and the molecular mechanism of their action using in vitro and in vivo models. Exposure SCC4 and SCC9 human oral cancer cells to the ω3-PUFA docosahexaenoic acid (DHA) reduced cell viability in a dose- and time-dependent manner. The increase in cell death was due in part to apoptosis, since cells incubated with DHA exhibited elevated levels of apoptotic markers including cleaved PARP expression, subG1 DNA portion and TUNEL-positive nuclei. DHA treatment also led to autophagic vesicle formation and an increase in autophagic flux, indicating the involvement of both apoptosis and autophagy in the cytotoxic effect of ω3-PUFAs on oral cancer cells. Further experiments revealed that the concurrent activation of apoptosis and autophagy induced by DHA was linked to reactive oxygen species (ROS) overproduction and inhibition of Akt/mTOR signaling molecules. Moreover, stable SCC9 cell lines expressing the ω3-desaturase gene (SCC9-fsc) or control vector (SCC9-csc) were generated, and the effect of endogenous high level of ω3-PUFAs was investigated. The growth rate and colony-forming capacity of SCC9-fsc were remarkably decreased compared to those of SCC9-csc. Likewise, tumor size and volume of SCC9-fsc implanted into nude mice were also significantly inhibited with increases in the cell death index. Taken together, these results indicate that ω3-PUFAs induce apoptosis- and autophagy-associated cell death through ROS and Akt/mTOR signaling pathways in oral cancer cells. Thus, utilization of ω3-PUFAs may represent a promising therapeutic approach for chemoprevention and treatment of human oral cancer. [This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No. 2011-0013263 and 2007-0054932).] Citation Format: Kyu Lim, Soyeon Shin, Tae-Hwa Hong, Kaipeng Jing, Soyeon Jeong, Soyeon Kim, Gi-Ryang Kweon, Seung-Kiel Park, Jong-Il Park. Omega-3 polyunsaturated fatty acids induce apoptotic and autophagic cell death through inhibition of Akt/mTOR pathway in human oral cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5121. doi:10.1158/1538-7445.AM2014-5121