Purposes of the study: Our clinical results show that obese patients with cervical cancer who are treated with definitive chemoradiation have favorable outcomes, and this effect is independent of diabetes or metformin use. PI3K/AKT pathway signaling is decreased in cervical tumors from obese hosts, even in the context of genomic mutations that would otherwise activate PI3K signaling, such as PTEN deletion. The objective of the present study is to determine whether other factors related to obesity, such as circulating free fatty acids, influence radiation responses in vitro.
Experimental procedures: Radiation sensitivity experiments were performed in cervical cancer cells with and without PI3K pathway mutations (CaSki (mutant), ME180 (mutant), SiHa (WT). To determine whether combination treatment of free fatty acids (palmitic, oleic and linoleic) plus radiation increases cytotoxicity in cervical cells, we performed cell viability assay, long term colony formation assays (CFA) and morphological examination by vertical microscope. To determine whether the addition of free fatty acids to radiation influences cell survival signaling, a series of Western blots were performed.
Summary: We observed that combination treatment of free fatty acids and radiation significantly increased cytotoxicity in all the cervical cancer cell lines tested. Mechanistic investigations revealed that free fatty acids induced potentiation of radiation-induced cytotoxicity through downregulation of p-mTOR, p-Akt and PTEN. Furthermore, we observed that this combination regimen upregulates the expression PPARγ and p53.
Conclusions: Free fatty acids potentiated the effect of radiation in PI3K-activated cervical cancer cell lines through mTOR/Akt//PPARg/p53 mediated pathway. Future studies will characterize the mechanism of free fatty acid potentiation of radiation-induced tumor cell death in detail, including the potential contribution of lipid peroxidation and alterations in glucose metabolism.
Citation Format: Naoshad Muhammad, Ramachandran Rashmi, Fiona Ruiz, Michael C. Zahner, Julie K. Schwarz. Free fatty acids augment radiation-induced cytotoxicity in cervical cancer cells via mTOR/Akt//PPARg/p53-mediated pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5463.