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2016 ; 12
(7
): 786-98
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Fenofibrate Suppresses Oral Tumorigenesis via Reprogramming Metabolic Processes:
Potential Drug Repurposing for Oral Cancer
#MMPMID27313493
Jan CI
; Tsai MH
; Chiu CF
; Huang YP
; Liu CJ
; Chang NW
Int J Biol Sci
2016[]; 12
(7
): 786-98
PMID27313493
show ga
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.
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