1. Department of Pathology, China Medical University and Hospital, Taichung, Taiwan, ROC
2. Department of Pathology, China Medical University and Beigang Hospital, Yunlin, Taiwan.TOC.
3. Department of Otolaryngology, China Medical University and Hospital, Taichung, Taiwan, ROC.
4. Department of Hematology Oncology, China Medical University and Hospital, Taichung, Taiwan, ROC.
5. Department of Physiology, College of Medicine, China Medical University, Taichung, Taiwan, ROC.
6. Department of Biochemistry, College of Medicine, China Medical University, Taichung, Taiwan, ROC.
One anticancer strategy suggests targeting mitochondrial metabolism to trigger cell death through slowing down energy production from the Warburg effect. Fenofibrate is a clinical lipid-lowering agent and an effective anticancer drug. In the present study, we demonstrate that fenofibrate provided novel mechanisms for delaying oral tumor development via the reprogramming of metabolic processes. Fenofibrate induced cytotoxicity by decreasing oxygen consumption rate (OCR) that was accompanied with increasing extracellular acidification rate (ECAR) and reducing ATP content. Moreover, fenofibrate caused changes in the protein expressions of hexokinase II (HK II), pyruvate kinase, pyruvate dehydrogenase, and voltage-dependent anion channel (VDAC), which are associated with the Warburg effect. In addition, fenofibrate reprogrammed the metabolic pathway by interrupting the binding of HK II to VDAC. In an oral cancer mouse model, fenofibrate exhibited both preventive and therapeutic efficacy on oral tumorigenesis. Fenofibrate administration suppressed the incidence rate of tongue lesions, reduced the tumor sizes, decreased the tumor multiplicity, and decreased the immunoreactivities of VDAC and mTOR. The molecular mechanisms involved in fenofibrate's ability to delay tumor development included the down-regulation of mTOR activity via TSC1/2-dependent signaling through activation of AMPK and inactivation of Akt, or via a TSC1/2-independent pathway through direct suppression of raptor. Our findings provide a molecular rationale whereby fenofibrate exerts anticancer and additional beneficial effects for the treatment of oral cancer patients.
Keywords: Fenofibrate, Oral cancer, Warburg effect, Metabolic reprogramming, mTOR