{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T01:59:51Z","timestamp":1773885591026,"version":"3.50.1"},"reference-count":38,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2023,4,4]],"date-time":"2023-04-04T00:00:00Z","timestamp":1680566400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Genes to Cells"],"published-print":{"date-parts":[[2023,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The tuberous sclerosis complex (TSC) gene products (TSC1\/TSC2) negatively regulate mTORC1. Although mTORC1 inhibitors are used for the treatment of TSC, incomplete tumor elimination and the adverse effects from long\u2010term administration are problems that need to be solved. Branched\u2010chain amino acid (BCAA) metabolism is involved in the growth of many tumor cells via the mTORC1 pathway. However, it remains unclear how BCAA metabolism affects the growth of mTORC1\u2010dysregulated tumors. We show here that the expression of branched\u2010chain amino transferase1 (Bcat1) was suppressed in <jats:italic>Tsc2<\/jats:italic>\u2010deficient murine renal tumor cells either by treatment with rapamycin or restoration of Tsc2 expression suggesting that Bcat1 is located downstream of Tsc2\u2010mTORC1 pathway. We also found that gabapentin, a Bcat1 inhibitor suppressed the growth of <jats:italic>Tsc2<\/jats:italic>\u2010deficient tumor cells and increased efficacy when combined with rapamycin. We investigate the functional importance of Bcat1 and the mitochondrial isoform Bcat2 by inhibiting each enzyme separately or both together by genome editing and shRNA in <jats:italic>Tsc2<\/jats:italic>\u2010deficient cells. We found that deficiency of both enzymes, but not either alone, inhibited cell growth, indicating that BCAA\u2010metabolic reactions support <jats:italic>Tsc2<\/jats:italic>\u2010deficient cell proliferation. Our results indicate that inhibition of Bcat1 and Bcat2 by specific drugs should be a useful method for TSC treatment.<\/jats:p>","DOI":"10.1111\/gtc.13027","type":"journal-article","created":{"date-parts":[[2023,3,25]],"date-time":"2023-03-25T19:44:12Z","timestamp":1679773452000},"page":"447-456","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Bcat1 is controlled by Tsc2\/<scp>mTORC1<\/scp> pathway at expression levels and its deficiency together with Bcat2 inactivation suppresses the growth of a <scp><i>Tsc2<\/i><sup>\u2212\/\u2212<\/sup><\/scp> tumor cell line"],"prefix":"10.1111","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5957-4717","authenticated-orcid":false,"given":"Keiko","family":"Nishikawa","sequence":"first","affiliation":[{"name":"Department of Molecular Pathogenesis Juntendo University Graduate School of Medicine, 2\u20101\u20101 Hongo, Bunkyo\u2010ku, Tokyo 113\u20108421  Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshihiro","family":"Mezawa","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathogenesis Juntendo University Graduate School of Medicine, 2\u20101\u20101 Hongo, Bunkyo\u2010ku, Tokyo 113\u20108421  Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshiyuki","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathogenesis Juntendo University Graduate School of Medicine, 2\u20101\u20101 Hongo, Bunkyo\u2010ku, Tokyo 113\u20108421  Japan"},{"name":"Department of Pathology and Oncology Juntendo University Faculty of Medicine, 2\u20101\u20101 Hongo, Bunkyo\u2010ku, Tokyo 113\u20108421  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