PMID- 29721083
OWN - NLM
STAT- MEDLINE
DCOM- 20190412
LR  - 20210503
IS  - 1838-7640 (Electronic)
IS  - 1838-7640 (Linking)
VI  - 8
IP  - 9
DP  - 2018
TI  - Targeting CPT1A-mediated fatty acid oxidation sensitizes nasopharyngeal carcinoma 
      to radiation therapy.
PG  - 2329-2347
LID - 10.7150/thno.21451 [doi]
AB  - Nasopharyngeal carcinoma (NPC) has a particularly high prevalence in southern 
      China, southeastern Asia and northern Africa. Radiation resistance remains a 
      serious obstacle to successful treatment in NPC. This study aimed to explore the 
      metabolic feature of radiation-resistant NPC cells and identify new 
      molecular-targeted agents to improve the therapeutic effects of radiotherapy in 
      NPC. Methods: Radiation-responsive and radiation-resistant NPC cells were used as 
      the model system in vitro and in vivo. Metabolomics approach was used to 
      illustrate the global metabolic changes. (13)C isotopomer tracing experiment and 
      Seahorse XF analysis were undertaken to determine the activity of fatty acid 
      oxidation (FAO). qRT-PCR was performed to evaluate the expression of essential 
      FAO genes including CPT1A. NPC tumor tissue microarray was used to investigate 
      the prognostic role of CPT1A. Either RNA interference or pharmacological blockade 
      by Etomoxir were used to inhibit CPT1A. Radiation resistance was evaluated by 
      colony formation assay. Mitochondrial membrane potential, apoptosis and neutral 
      lipid content were measured by flow cytometry analysis using JC-1, Annexin V and 
      LipidTOX Red probe respectively. Molecular markers of mitochondrial apoptosis 
      were detected by western blot. Xenografts were treated with Etomoxir, radiation, 
      or a combination of Etomoxir and radiation. Mitochondrial apoptosis and lipid 
      droplets content of tumor tissues were detected by cleaved caspase 9 and Oil Red 
      O staining respectively. Liquid chromatography coupled with tandem mass 
      spectrometry approach was used to identify CPT1A-binding proteins. The 
      interaction of CPT1A and Rab14 were detected by immunoprecipitation, 
      immunofluorescence and in situ proximity ligation analysis. Fragment docking and 
      direct coupling combined computational protein-protein interaction prediction 
      method were used to predict the binding interface. Fatty acid trafficking was 
      measured by pulse-chase assay using BODIPY C16 and MitoTracker Red probe. 
      Results: FAO was active in radiation-resistant NPC cells, and the rate-limiting 
      enzyme of FAO, carnitine palmitoyl transferase 1 A (CPT1A), was consistently 
      up-regulated in these cells. The protein level of CPT1A was significantly 
      associated with poor overall survival of NPC patients following radiotherapy. 
      Inhibition of CPT1A re-sensitized NPC cells to radiation therapy by activating 
      mitochondrial apoptosis both in vitro and in vivo. In addition, we identified 
      Rab14 as a novel CPT1A binding protein. The CPT1A-Rab14 interaction facilitated 
      fatty acid trafficking from lipid droplets to mitochondria, which decreased 
      radiation-induced lipid accumulation and maximized ATP production. Knockdown of 
      Rab14 attenuated CPT1A-mediated fatty acid trafficking and radiation resistance. 
      Conclusion: An active FAO is a vital signature of NPC radiation resistance. 
      Targeting CPT1A could be a beneficial regimen to improve the therapeutic effects 
      of radiotherapy in NPC patients. Importantly, the CPT1A-Rab14 interaction plays 
      roles in CPT1A-mediated radiation resistance by facilitating fatty acid 
      trafficking. This interaction could be an attractive interface for the discovery 
      of novel CPT1A inhibitors.
FAU - Tan, Zheqiong
AU  - Tan Z
AD  - Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, 
      Xiangya Hospital, Central South University, Changsha 410078, China.
AD  - Cancer Research Institute, Xiangya School of Medicine, Central South University, 
      Changsha 410078, China.
AD  - Key Laboratory of Carcinogenesis, Chinese Ministry of Health, Changsha 410078, 
      China.
FAU - Xiao, Lanbo
AU  - Xiao L
AD  - Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, 
      Xiangya Hospital, Central South University, Changsha 410078, China.
AD  - Cancer Research Institute, Xiangya School of Medicine, Central South University, 
      Changsha 410078, China.
AD  - Key Laboratory of Carcinogenesis, Chinese Ministry of Health, Changsha 410078, 
      China.
FAU - Tang, Min
AU  - Tang M
AD  - Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, 
      Xiangya Hospital, Central South University, Changsha 410078, China.
AD  - Cancer Research Institute, Xiangya School of Medicine, Central South University, 
      Changsha 410078, China.
AD  - Key Laboratory of Carcinogenesis, Chinese Ministry of Health, Changsha 410078, 
      China.
FAU - Bai, Fang
AU  - Bai F
AD  - Center for Theoretical Biological Physics, Rice University, Houston, Texas 77005, 
      USA.
FAU - Li, Jiangjiang
AU  - Li J
AD  - Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, 
      Xiangya Hospital, Central South University, Changsha 410078, China.
AD  - Cancer Research Institute, Xiangya School of Medicine, Central South University, 
      Changsha 410078, China.
AD  - Key Laboratory of Carcinogenesis, Chinese Ministry of Health, Changsha 410078, 
      China.
AD  - Research Center for Technologies of Nucleic Acid-Based Diagnostics and 
      Therapeutics Hunan Province, Changsha 410078, China.
FAU - Li, Liling
AU  - Li L
AD  - Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, 
      Xiangya Hospital, Central South University, Changsha 410078, China.
AD  - Cancer Research Institute, Xiangya School of Medicine, Central South University, 
      Changsha 410078, China.
AD  - Key Laboratory of Carcinogenesis, Chinese Ministry of Health, Changsha 410078, 
      China.
FAU - Shi, Feng
AU  - Shi F
AD  - Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, 
      Xiangya Hospital, Central South University, Changsha 410078, China.
AD  - Cancer Research Institute, Xiangya School of Medicine, Central South University, 
      Changsha 410078, China.
AD  - Key Laboratory of Carcinogenesis, Chinese Ministry of Health, Changsha 410078, 
      China.
FAU - Li, Namei
AU  - Li N
AD  - Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, 
      Xiangya Hospital, Central South University, Changsha 410078, China.
AD  - Cancer Research Institute, Xiangya School of Medicine, Central South University, 
      Changsha 410078, China.
AD  - Key Laboratory of Carcinogenesis, Chinese Ministry of Health, Changsha 410078, 
      China.
FAU - Li, Yueshuo
AU  - Li Y
AD  - Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, 
      Xiangya Hospital, Central South University, Changsha 410078, China.
AD  - Cancer Research Institute, Xiangya School of Medicine, Central South University, 
      Changsha 410078, China.
AD  - Key Laboratory of Carcinogenesis, Chinese Ministry of Health, Changsha 410078, 
      China.
FAU - Du, Qianqian
AU  - Du Q
AD  - Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, 
      Xiangya Hospital, Central South University, Changsha 410078, China.
AD  - Cancer Research Institute, Xiangya School of Medicine, Central South University, 
      Changsha 410078, China.
AD  - Key Laboratory of Carcinogenesis, Chinese Ministry of Health, Changsha 410078, 
      China.
FAU - Lu, Jingchen
AU  - Lu J
AD  - Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, 
      Xiangya Hospital, Central South University, Changsha 410078, China.
AD  - Cancer Research Institute, Xiangya School of Medicine, Central South University, 
      Changsha 410078, China.
AD  - Key Laboratory of Carcinogenesis, Chinese Ministry of Health, Changsha 410078, 
      China.
FAU - Weng, Xinxian
AU  - Weng X
AD  - Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, 
      Xiangya Hospital, Central South University, Changsha 410078, China.
AD  - Cancer Research Institute, Xiangya School of Medicine, Central South University, 
      Changsha 410078, China.
AD  - Key Laboratory of Carcinogenesis, Chinese Ministry of Health, Changsha 410078, 
      China.
FAU - Yi, Wei
AU  - Yi W
AD  - Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, 
      Xiangya Hospital, Central South University, Changsha 410078, China.
AD  - Cancer Research Institute, Xiangya School of Medicine, Central South University, 
      Changsha 410078, China.
AD  - Key Laboratory of Carcinogenesis, Chinese Ministry of Health, Changsha 410078, 
      China.
FAU - Zhang, Hanwen
AU  - Zhang H
AD  - Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha 
      410078, China.
FAU - Fan, Jia
AU  - Fan J
AD  - Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory 
      for Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Shanghai 
      200000, China.
FAU - Zhou, Jian
AU  - Zhou J
AD  - Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory 
      for Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Shanghai 
      200000, China.
FAU - Gao, Qiang
AU  - Gao Q
AD  - Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory 
      for Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Shanghai 
      200000, China.
FAU - Onuchic, Jose N
AU  - Onuchic JN
AD  - Center for Theoretical Biological Physics, Rice University, Houston, Texas 77005, 
      USA.
FAU - Bode, Ann M
AU  - Bode AM
AD  - The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
FAU - Luo, Xiangjian
AU  - Luo X
AD  - Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, 
      Xiangya Hospital, Central South University, Changsha 410078, China.
AD  - Cancer Research Institute, Xiangya School of Medicine, Central South University, 
      Changsha 410078, China.
AD  - Key Laboratory of Carcinogenesis, Chinese Ministry of Health, Changsha 410078, 
      China.
FAU - Cao, Ya
AU  - Cao Y
AD  - Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, 
      Xiangya Hospital, Central South University, Changsha 410078, China.
AD  - Cancer Research Institute, Xiangya School of Medicine, Central South University, 
      Changsha 410078, China.
AD  - Key Laboratory of Carcinogenesis, Chinese Ministry of Health, Changsha 410078, 
      China.
AD  - Research Center for Technologies of Nucleic Acid-Based Diagnostics and 
      Therapeutics Hunan Province, Changsha 410078, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20180322
PL  - Australia
TA  - Theranostics
JT  - Theranostics
JID - 101552395
RN  - 0 (Fatty Acids)
RN  - EC 2.3.1.21 (CPT1A protein, human)
RN  - EC 2.3.1.21 (Carnitine O-Palmitoyltransferase)
SB  - IM
MH  - Apoptosis/radiation effects
MH  - Carnitine O-Palmitoyltransferase/*metabolism
MH  - Cell Line, Tumor
MH  - Fatty Acids/*metabolism
MH  - Humans
MH  - Lipid Metabolism/radiation effects
MH  - Mitochondria/metabolism/radiation effects
MH  - Nasopharyngeal Carcinoma/metabolism/*radiotherapy
MH  - Nasopharyngeal Neoplasms/metabolism/*radiotherapy
MH  - Oxidation-Reduction
MH  - Radiation Tolerance/radiation effects
PMC - PMC5928893
OTO - NOTNLM
OT  - CPT1A
OT  - Rab14
OT  - fatty acid oxidation
OT  - fatty acid trafficking
OT  - nasopharyngeal carcinoma
OT  - radiation therapy
COIS- Competing Interests: The authors have declared that no competing interest exists.
EDAT- 2018/05/04 06:00
MHDA- 2019/04/13 06:00
PMCR- 2018/01/01
CRDT- 2018/05/04 06:00
PHST- 2017/06/13 00:00 [received]
PHST- 2018/02/28 00:00 [accepted]
PHST- 2018/05/04 06:00 [entrez]
PHST- 2018/05/04 06:00 [pubmed]
PHST- 2019/04/13 06:00 [medline]
PHST- 2018/01/01 00:00 [pmc-release]
AID - thnov08p2329 [pii]
AID - 10.7150/thno.21451 [doi]
PST - epublish
SO  - Theranostics. 2018 Mar 22;8(9):2329-2347. doi: 10.7150/thno.21451. eCollection 
      2018.