PMID- 27313493
OWN - NLM
STAT- MEDLINE
DCOM- 20171107
LR  - 20220310
IS  - 1449-2288 (Electronic)
IS  - 1449-2288 (Linking)
VI  - 12
IP  - 7
DP  - 2016
TI  - Fenofibrate Suppresses Oral Tumorigenesis via Reprogramming Metabolic Processes: 
      Potential Drug Repurposing for Oral Cancer.
PG  - 786-98
LID - 10.7150/ijbs.13851 [doi]
AB  - 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.
FAU - Jan, Chia-Ing
AU  - Jan CI
AD  - 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.
FAU - Tsai, Ming-Hsui
AU  - Tsai MH
AD  - 3. Department of Otolaryngology, China Medical University and Hospital, Taichung, 
      Taiwan, ROC.
FAU - Chiu, Chang-Fang
AU  - Chiu CF
AD  - 4. Department of Hematology Oncology, China Medical University and Hospital, 
      Taichung, Taiwan, ROC.
FAU - Huang, Yi-Ping
AU  - Huang YP
AD  - 5. Department of Physiology, College of Medicine, China Medical University, 
      Taichung, Taiwan, ROC.
FAU - Liu, Chia Jen
AU  - Liu CJ
AD  - 6. Department of Biochemistry, College of Medicine, China Medical University, 
      Taichung, Taiwan, ROC.
FAU - Chang, Nai Wen
AU  - Chang NW
AD  - 6. Department of Biochemistry, College of Medicine, China Medical University, 
      Taichung, Taiwan, ROC.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20160515
PL  - Australia
TA  - Int J Biol Sci
JT  - International journal of biological sciences
JID - 101235568
RN  - 0 (Antineoplastic Agents)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - EC 2.7.1.1 (Hexokinase)
RN  - U202363UOS (Fenofibrate)
SB  - IM
MH  - Adenosine Triphosphate/metabolism
MH  - Animals
MH  - Antineoplastic Agents/*therapeutic use
MH  - Blotting, Western
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cell Survival/drug effects/genetics
MH  - Cell Transformation, Neoplastic/drug effects/genetics
MH  - Fenofibrate/*therapeutic use
MH  - Hexokinase/metabolism
MH  - Humans
MH  - Immunohistochemistry
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mouth Neoplasms/*drug therapy/*metabolism
MH  - Oxygen Consumption/drug effects
PMC - PMC4910598
OTO - NOTNLM
OT  - Fenofibrate
OT  - Metabolic reprogramming
OT  - Oral cancer
OT  - Warburg effect
OT  - mTOR
COIS- Competing Interests: The authors have declared that no competing interest exists.
EDAT- 2016/06/18 06:00
MHDA- 2017/11/08 06:00
PMCR- 2016/01/01
CRDT- 2016/06/18 06:00
PHST- 2015/09/14 00:00 [received]
PHST- 2016/04/01 00:00 [accepted]
PHST- 2016/06/18 06:00 [entrez]
PHST- 2016/06/18 06:00 [pubmed]
PHST- 2017/11/08 06:00 [medline]
PHST- 2016/01/01 00:00 [pmc-release]
AID - ijbsv12p0786 [pii]
AID - 10.7150/ijbs.13851 [doi]
PST - epublish
SO  - Int J Biol Sci. 2016 May 15;12(7):786-98. doi: 10.7150/ijbs.13851. eCollection 
      2016.