Targeting CPT1A-mediated fatty acid oxidation sensitizes nasopharyngeal carcinoma to radiation therapy

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dc.citation.firstpage2329en_US
dc.citation.issueNumber9en_US
dc.citation.journalTitleTheranosticsen_US
dc.citation.lastpage2347en_US
dc.citation.volumeNumber8en_US
dc.contributor.authorTan, Zheqiongen_US
dc.contributor.authorXiao, Lanboen_US
dc.contributor.authorTang, Minen_US
dc.contributor.authorBai, Fangen_US
dc.contributor.authorLi, Jiangjiangen_US
dc.contributor.authorLi, Lilingen_US
dc.contributor.authorShi, Fengen_US
dc.contributor.authorLi, Nameien_US
dc.contributor.authorLi, Yueshuoen_US
dc.contributor.authorDu, Qianqianen_US
dc.contributor.authorLu, Jingchenen_US
dc.contributor.authorWeng, Xinxianen_US
dc.contributor.authorYi, Weien_US
dc.contributor.authorZhang, Hanwenen_US
dc.contributor.authorFan, Jiaen_US
dc.contributor.authorZhou, Jianen_US
dc.contributor.authorGao, Qiangen_US
dc.contributor.authorOnuchic, José N.en_US
dc.contributor.authorBode, Ann M.en_US
dc.contributor.authorLuo, Xiangjianen_US
dc.contributor.authorCao, Yaen_US
dc.date.accessioned2018-07-16T21:54:26Zen_US
dc.date.available2018-07-16T21:54:26Zen_US
dc.date.issued2018en_US
dc.description.abstractNasopharyngeal 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. 13C 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.en_US
dc.identifier.citationTan, Zheqiong, Xiao, Lanbo, Tang, Min, et al.. "Targeting CPT1A-mediated fatty acid oxidation sensitizes nasopharyngeal carcinoma to radiation therapy." <i>Theranostics,</i> 8, no. 9 (2018) Ivyspring: 2329-2347. https://doi.org/10.7150/thno.21451.en_US
dc.identifier.doihttps://doi.org/10.7150/thno.21451en_US
dc.identifier.urihttps://hdl.handle.net/1911/102445en_US
dc.language.isoengen_US
dc.publisherIvyspringen_US
dc.rightsThis is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). en_US
dc.rights.urihttps://creativecommons.org/licenses/by-nc/4.0/en_US
dc.subject.keywordCPT1Aen_US
dc.subject.keywordfatty acid oxidationen_US
dc.subject.keywordnasopharyngeal carcinomaen_US
dc.subject.keywordradiation therapyen_US
dc.subject.keywordRab14en_US
dc.subject.keywordfatty acid traffickingen_US
dc.titleTargeting CPT1A-mediated fatty acid oxidation sensitizes nasopharyngeal carcinoma to radiation therapyen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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