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The main etiology of TSC is the loss\u2010of\u2010function mutation of <jats:italic>TSC1<\/jats:italic> or <jats:italic>TSC2<\/jats:italic> gene, which leads to aberrant activation of mammalian target of rapamycin complex 1 (mTORC1). In this research, we found a significant increase of 6\u2010phosphofructo\u20102\u2010kinase\/fructose\u20102,6\u2010biphosphatase 3 (PFKFB3) expression in Tsc1\u2212\/\u2212 and Tsc2\u2212\/\u2212 mouse embryonic fibroblasts (MEFs) compared with the control cells. Inhibition of mTORC1 led to a dramatic decrease of PFKFB3 expression, indicating PFKFB3 regulation by mTORC1. Moreover, suppression of mTORC1 inhibited the expression of PFKFB3 in rat uterine leiomyoma\u2010derived Tsc2\u2010null ELT3 cells and human tumor cells. Furthermore, we identified hypoxia\u2010inducible factor 1\u03b1 (HIF\u20101\u03b1) as a mediator transmitting the signal from mTORC1 to PFKFB3. Depletion of PFKFB3 inhibited proliferation and tumorigenicity of Tsc1\u2010 or Tsc2\u2010deficient cells. In addition, combination of rapamycin with PFK15, a PFKFB3 inhibitor, exerts a stronger inhibitory effect on cell proliferation of Tsc1\u2010 or Tsc2\u2010null MEFs than treatment with single drug. We conclude that loss of TSC1 or TSC2 led to upregulated expression of PFKFB3 through activation of mTORC1\/HIF\u20101\u03b1 signaling pathway and co\u2010administration of rapamycin and PFK15 may be a promising strategy for the treatment of TSC tumors as well as other hyperactivated mTORC1\u2010related tumors.<\/jats:p>","DOI":"10.1002\/iub.2232","type":"journal-article","created":{"date-parts":[[2020,1,20]],"date-time":"2020-01-20T11:19:39Z","timestamp":1579519179000},"page":"965-977","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Upregulation of 6\u2010phosphofructo\u20102\u2010kinase (PFKFB3) by hyperactivated mammalian target of rapamycin complex 1 is critical for tumor growth in tuberous sclerosis complex"],"prefix":"10.1002","volume":"72","author":[{"given":"Yani","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Biochemistry &amp; Molecular Biology, School of Basic Medicine Anhui 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