{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T23:15:20Z","timestamp":1792278920176,"version":"4.4.0"},"reference-count":36,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2021,2,10]],"date-time":"2021-02-10T00:00:00Z","timestamp":1612915200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,2,10]],"date-time":"2021-02-10T00:00:00Z","timestamp":1612915200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["No. 81672385"],"award-info":[{"award-number":["No. 81672385"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004731","name":"Natural Science Foundation of Zhejiang Province","doi-asserted-by":"publisher","award":["No.LY18H160048"],"award-info":[{"award-number":["No.LY18H160048"]}],"id":[{"id":"10.13039\/501100004731","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007194","name":"Wenzhou Municipal Science and Technology Bureau","doi-asserted-by":"publisher","award":["No. Y2020158"],"award-info":[{"award-number":["No. Y2020158"]}],"id":[{"id":"10.13039\/501100007194","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Cisplatin is one of the most effective chemotherapy drugs and is widely used in the treatment of cancer, including hepatocellular carcinoma (HCC) and cervical cancer, but its therapeutic benefit is limited by the development of resistance. Our previous studies demonstrated that BCAT1 promoted cell proliferation and decreased cisplatin sensitivity in HCC cells. However, the exact role and mechanism of how BCAT1 is involved in cisplatin cytotoxicity remain undefined. In this study, we revealed that cisplatin triggered autophagy in cancer cells, with an increase in BCAT1 expression. The cisplatin-induced up-regulation of BCAT1 decreased the cisplatin sensitivity by regulating autophagy through the mTOR signaling pathway. In addition, branched-chain amino acids or leucine treatment inhibited cisplatin- or BCAT1-mediated autophagy and increased cisplatin sensitivity by activating mTOR signaling in cancer cells. Moreover, inhibition of autophagy by chloroquine increased cisplatin sensitivity in vivo. Also, the knockdown of BCAT1 or the administration of leucine activated mTOR signaling, inhibited autophagy, and increased cisplatin sensitivity in cancer cells in vivo. These findings demonstrate a new mechanism, revealing that BCAT1 decreases cisplatin sensitivity in cancer cells by inducing mTOR-mediated autophagy <jats:italic>via<\/jats:italic> branched-chain amino acid leucine metabolism, providing an attractive pharmacological target to improve the effectiveness of chemotherapy.<\/jats:p>","DOI":"10.1038\/s41419-021-03456-7","type":"journal-article","created":{"date-parts":[[2021,2,11]],"date-time":"2021-02-11T00:11:40Z","timestamp":1613002300000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":90,"title":["BCAT1 decreases the sensitivity of cancer cells to cisplatin by regulating mTOR-mediated autophagy via branched-chain amino acid metabolism"],"prefix":"10.1038","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6309-6500","authenticated-orcid":false,"given":"Lifang","family":"Luo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjing","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2856-3492","authenticated-orcid":false,"given":"Weijian","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2461-7606","authenticated-orcid":false,"given":"Shuhan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6192-8297","authenticated-orcid":false,"given":"Wenqi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2478-8635","authenticated-orcid":false,"given":"Xiaohui","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daoquan","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4737-4320","authenticated-orcid":false,"given":"Tan Hooi Min","family":"Grahn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9588-2015","authenticated-orcid":false,"given":"Lei","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9769-1244","authenticated-orcid":false,"given":"Yihu","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,2,10]]},"reference":[{"key":"3456_CR1","doi-asserted-by":"publisher","first-page":"102925","DOI":"10.1016\/j.bioorg.2019.102925","volume":"88","author":"S Ghosh","year":"2019","unstructured":"Ghosh, S. Cisplatin: the first metal based anticancer drug. Bioorg. Chem. 88, 102925 (2019).","journal-title":"Bioorg. Chem."},{"key":"3456_CR2","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1016\/j.biopha.2018.12.010","volume":"110","author":"CY Sun","year":"2019","unstructured":"Sun, C. Y., Zhang, Q. Y., Zheng, G. J. & Feng, B. Phytochemicals: current strategy to sensitize cancer cells to cisplatin. Biomed. Pharmacother. 110, 518\u2013527 (2019).","journal-title":"Biomed. Pharmacother."},{"key":"3456_CR3","doi-asserted-by":"publisher","first-page":"69606","DOI":"10.18632\/oncotarget.11901","volume":"7","author":"HR Cho","year":"2016","unstructured":"Cho, H. R. et al. Assessment of bevacizumab resistance increased by expression of BCAT1 in IDH1 wild-type glioblastoma: application of DSC perfusion MR imaging. Oncotarget 7, 69606\u201369615 (2016).","journal-title":"Oncotarget"},{"key":"3456_CR4","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1016\/j.bbrc.2017.02.101","volume":"486","author":"L Zhang","year":"2017","unstructured":"Zhang, L. & Han, J. Branched-chain amino acid transaminase 1 (BCAT1) promotes the growth of breast cancer cells through improving mTOR-mediated mitochondrial biogenesis and function. Biochem Biophys. Res. Commun. 486, 224\u2013231 (2017).","journal-title":"Biochem Biophys. Res. Commun."},{"key":"3456_CR5","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/j.humpath.2018.02.003","volume":"75","author":"Y Xu","year":"2018","unstructured":"Xu, Y. et al. Overexpression of BCAT1 is a prognostic marker in gastric cancer. Hum. Pathol. 75, 41\u201346 (2018).","journal-title":"Hum. Pathol."},{"key":"3456_CR6","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-019-5815-x","volume":"19","author":"B Zeng","year":"2019","unstructured":"Zeng, B. et al. The role of DNMT1\/hsa-miR-124-3p\/BCAT1 pathway in regulating growth and invasion of esophageal squamous cell carcinoma. BMC Cancer 19, 609 (2019).","journal-title":"BMC Cancer"},{"key":"3456_CR7","doi-asserted-by":"publisher","first-page":"3583","DOI":"10.2147\/OTT.S237306","volume":"13","author":"X Lin","year":"2020","unstructured":"Lin, X., Tan, S., Fu, L. & Dong, Q. BCAT1 overexpression promotes proliferation, invasion, and Wnt signaling in non-small cell lung cancers. Onco. Targets Ther. 13, 3583\u20133594 (2020).","journal-title":"Onco. Targets Ther."},{"key":"3456_CR8","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1038\/s42255-020-0226-5","volume":"2","author":"Z Zhu","year":"2020","unstructured":"Zhu, Z. et al. Tumour-reprogrammed stromal BCAT1 fuels branched-chain ketoacid dependency in stromal-rich PDAC tumours. Nat. Metab. 2, 775\u2013792 (2020).","journal-title":"Nat. Metab."},{"key":"3456_CR9","doi-asserted-by":"publisher","first-page":"1570","DOI":"10.1002\/mc.22612","volume":"56","author":"W Zhu","year":"2017","unstructured":"Zhu, W., Shao, Y. & Peng, Y. MicroRNA-218 inhibits tumor growth and increases chemosensitivity to CDDP treatment by targeting BCAT1 in prostate cancer. Mol. Carcinog. 56, 1570\u20131577 (2017).","journal-title":"Mol. Carcinog."},{"key":"3456_CR10","first-page":"725","volume":"49","author":"S-H Wu","year":"2018","unstructured":"Wu, S.-H., Zeng, X.-F., Wang, P., Zhou, Y. & Lin, W. The Expression and Significance of c-myc and bcat1 in Cervical Cancer. Sichuan Da Xue Xue Bao Yi Xue Ban. 49, 725\u2013730 (2018).","journal-title":"Sichuan Da Xue Xue Bao Yi Xue Ban."},{"key":"3456_CR11","doi-asserted-by":"publisher","first-page":"1836","DOI":"10.1111\/liv.13178","volume":"36","author":"Y-H Zheng","year":"2016","unstructured":"Zheng, Y.-H. et al. BCAT1, a key prognostic predictor of hepatocellular carcinoma, promotes cell proliferation and induces chemoresistance to cisplatin. Liver Int. 36, 1836\u20131847 (2016).","journal-title":"Liver Int."},{"key":"3456_CR12","doi-asserted-by":"publisher","first-page":"2648","DOI":"10.3892\/ol.2016.4969","volume":"12","author":"M Xu","year":"2016","unstructured":"Xu, M. et al. BCAT1 promotes tumor cell migration and invasion in hepatocellular carcinoma. Oncol. Lett. 12, 2648\u20132656 (2016).","journal-title":"Oncol. Lett."},{"key":"3456_CR13","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1016\/j.celrep.2019.06.026","volume":"28","author":"Y Wang","year":"2019","unstructured":"Wang, Y. et al. Branched-chain amino acid metabolic reprogramming orchestrates drug resistance to EGFR tyrosine kinase inhibitors. Cell Rep. 28, 512\u2013525 (2019).","journal-title":"Cell Rep."},{"key":"3456_CR14","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms16040","volume":"8","author":"AE Papathanassiu","year":"2017","unstructured":"Papathanassiu, A. E. et al. BCAT1 controls metabolic reprogramming in activated human macrophages and is associated with inflammatory diseases. Nat. Commun. 8, 16040 (2017).","journal-title":"Nat. Commun."},{"key":"3456_CR15","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1007\/978-981-15-0602-4_3","volume":"1206","author":"Y Wang","year":"2019","unstructured":"Wang, Y. & Zhang, H. Regulation of autophagy by mTOR signaling pathway. Adv. Exp. Med Biol. 1206, 67\u201383 (2019).","journal-title":"Adv. Exp. Med Biol."},{"key":"3456_CR16","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms10043","volume":"6","author":"J Mansfeld","year":"2015","unstructured":"Mansfeld, J. et al. Branched-chain amino acid catabolism is a conserved regulator of physiological ageing. Nat. Commun. 6, 10043 (2015).","journal-title":"Nat. Commun."},{"key":"3456_CR17","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1172\/JCI73939","volume":"125","author":"YC Kim","year":"2015","unstructured":"Kim, Y. C. & Guan, K.-L. mTOR: a pharmacologic target for autophagy regulation. J. Clin. Invest. 125, 25\u201332 (2015).","journal-title":"J. Clin. Invest."},{"key":"3456_CR18","doi-asserted-by":"publisher","first-page":"528","DOI":"10.1038\/nrclinonc.2011.71","volume":"8","author":"F Janku","year":"2011","unstructured":"Janku, F., McConkey, D. J., Hong, D. S. & Kurzrock, R. Autophagy as a target for anticancer therapy. Nat. Rev. Clin. Oncol. 8, 528\u2013539 (2011).","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"3456_CR19","first-page":"355","volume":"78","author":"AA Parkhitko","year":"2013","unstructured":"Parkhitko, A. A., Favorova, O. O. & Henske, E. P. Autophagy: mechanisms, regulation, and its role in tumorigenesis. Biochemistry 78, 355\u2013367 (2013).","journal-title":"Biochemistry"},{"key":"3456_CR20","doi-asserted-by":"publisher","DOI":"10.1007\/s12032-015-0721-9","volume":"33","author":"J Liu","year":"2016","unstructured":"Liu, J., Fan, L., Wang, H. & Sun, G. Autophagy, a double-edged sword in anti-angiogenesis therapy. Med. Oncol. 33, 10 (2016).","journal-title":"Med. Oncol."},{"key":"3456_CR21","first-page":"220","volume":"1806","author":"S Chen","year":"2010","unstructured":"Chen, S. et al. Autophagy is a therapeutic target in anticancer drug resistance. Biochim Biophys. Acta 1806, 220\u2013229 (2010).","journal-title":"Biochim Biophys. Acta"},{"key":"3456_CR22","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2013.350","volume":"4","author":"X Sui","year":"2013","unstructured":"Sui, X. et al. Autophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment. Cell Death Dis. 4, e838 (2013).","journal-title":"Cell Death Dis."},{"key":"3456_CR23","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1016\/j.bcp.2013.12.009","volume":"87","author":"M Pennati","year":"2014","unstructured":"Pennati, M. et al. miR-205 impairs the autophagic flux and enhances cisplatin cytotoxicity in castration-resistant prostate cancer cells. Biochem. Pharm. 87, 579\u2013597 (2014).","journal-title":"Biochem. Pharm."},{"key":"3456_CR24","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1016\/j.canlet.2014.09.020","volume":"355","author":"L Yu","year":"2014","unstructured":"Yu, L. et al. Induction of autophagy counteracts the anticancer effect of cisplatin in human esophageal cancer cells with acquired drug resistance. Cancer Lett. 355, 34\u201345 (2014).","journal-title":"Cancer Lett."},{"key":"3456_CR25","doi-asserted-by":"publisher","first-page":"828","DOI":"10.1016\/j.gene.2015.11.013","volume":"576","author":"J Zhao","year":"2016","unstructured":"Zhao, J., Nie, Y., Wang, H. & Lin, Y. MiR-181a suppresses autophagy and sensitizes gastric cancer cells to cisplatin. Gene 576, 828\u2013833 (2016).","journal-title":"Gene"},{"key":"3456_CR26","doi-asserted-by":"publisher","first-page":"114003","DOI":"10.1016\/j.bcp.2020.114003","volume":"178","author":"R Hoffmann","year":"2020","unstructured":"Hoffmann, R. et al. Sulfated glycolipid PG545 induces endoplasmic reticulum stress and augments autophagic flux by enhancing anticancer chemotherapy efficacy in endometrial cancer. Biochem. Pharm. 178, 114003 (2020).","journal-title":"Biochem. Pharm."},{"key":"3456_CR27","doi-asserted-by":"publisher","first-page":"901","DOI":"10.1038\/nm.3217","volume":"19","author":"M T\u00f6njes","year":"2013","unstructured":"T\u00f6njes, M. et al. BCAT1 promotes cell proliferation through amino acid catabolism in gliomas carrying wild-type IDH1. Nat. Med. 19, 901\u2013908 (2013).","journal-title":"Nat. Med."},{"key":"3456_CR28","doi-asserted-by":"publisher","first-page":"1942","DOI":"10.1126\/science.1066015","volume":"294","author":"Y Fang","year":"2001","unstructured":"Fang, Y., Vilella-Bach, M., Bachmann, R., Flanigan, A. & Chen, J. Phosphatidic acid-mediated mitogenic activation of mTOR signaling. Science 294, 1942\u20131945 (2001).","journal-title":"Science"},{"key":"3456_CR29","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1038\/cdd.2008.110","volume":"16","author":"S Sarkar","year":"2009","unstructured":"Sarkar, S., Ravikumar, B., Floto, R. A. & Rubinsztein, D. C. Rapamycin and mTOR-independent autophagy inducers ameliorate toxicity of polyglutamine-expanded huntingtin and related proteinopathies. Cell Death Differ. 16, 46\u201356 (2009).","journal-title":"Cell Death Differ."},{"key":"3456_CR30","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1097\/MCO.0000000000000430","volume":"21","author":"EA Ananieva","year":"2018","unstructured":"Ananieva, E. A. & Wilkinson, A. C. Branched-chain amino acid metabolism in cancer. Curr. Opin. Clin. Nutr. Metab. Care 21, 64\u201370 (2018).","journal-title":"Curr. Opin. Clin. Nutr. Metab. Care"},{"key":"3456_CR31","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1016\/j.ccell.2019.12.011","volume":"37","author":"S Sivanand","year":"2020","unstructured":"Sivanand, S. & Vander Heiden, M. G. Emerging roles for branched-chain amino acid metabolism in cancer. Cancer Cell 37, 147\u2013156 (2020).","journal-title":"Cancer Cell"},{"key":"3456_CR32","doi-asserted-by":"publisher","first-page":"798S","DOI":"10.3945\/an.115.011221","volume":"7","author":"EA Ananieva","year":"2016","unstructured":"Ananieva, E. A., Powell, J. D. & Hutson, S. M. Leucine metabolism in T cell activation: mTOR signaling and beyond. Adv. Nutr. 7, 798S\u2013805S (2016).","journal-title":"Adv. Nutr."},{"key":"3456_CR33","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1016\/j.nut.2016.07.013","volume":"33","author":"S Nojiri","year":"2017","unstructured":"Nojiri, S., Fujiwara, K., Shinkai, N., Iio, E. & Joh, T. Effects of branched-chain amino acid supplementation after radiofrequency ablation for hepatocellular carcinoma: a randomized trial. Nutrition 33, 20\u201327 (2017).","journal-title":"Nutrition"},{"key":"3456_CR34","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1272\/jnms.83.248","volume":"83","author":"S Shiozawa","year":"2016","unstructured":"Shiozawa, S. et al. Impact of branched-chain amino acid-enriched nutrient on liver cirrhosis with hepatocellular carcinoma undergoing transcatheter arterial chemoembolization in Barcelona clinic liver cancer stage b: a prospective study. J. Nippon. Med. Sch. 83, 248\u2013256 (2016).","journal-title":"J. Nippon. Med. Sch."},{"key":"3456_CR35","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1126\/science.aab2674","volume":"351","author":"RL Wolfson","year":"2016","unstructured":"Wolfson, R. L. et al. Sestrin2 is a leucine sensor for the mTORC1 pathway. Science 351, 43\u201348 (2016).","journal-title":"Science"},{"key":"3456_CR36","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.cell.2015.08.068","volume":"163","author":"CP Day","year":"2015","unstructured":"Day, C. P., Merlino, G., Van & Dyke, T. Preclinical mouse cancer models: a maze of opportunities and challenges. Cell 163, 39\u201353 (2015).","journal-title":"Cell"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41419-021-03456-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-021-03456-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-021-03456-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,1]],"date-time":"2022-12-01T18:27:44Z","timestamp":1669919264000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41419-021-03456-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,10]]},"references-count":36,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2021,2]]}},"alternative-id":["3456"],"URL":"https:\/\/doi.org\/10.1038\/s41419-021-03456-7","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,10]]},"assertion":[{"value":"28 August 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 January 2021","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 January 2021","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 February 2021","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"All the animal experiments were approved by the Animal Experimental Ethics Committee of Wenzhou Medical University.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"This work is supported by Zhejiang Provincial Natural Science Foundation of China (No.LY18H160048), Wenzhou Municipal Sci-Tech Bureau Project (No. Y2020158), and National Natural Science Foundation of China (No. 81672385).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"The authors declare no conflict of interest.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"169"}}