Abstract
Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterized by the benign tumor formation in multiple organs. The main etiology of TSC is the loss-of-function mutation of TSC1 or TSC2 gene, which leads to aberrant activation of mammalian target of rapamycin complex 1 (mTORC1). In this research, we found a significant increase of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) expression in Tsc1-/- and Tsc2-/- 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-derived Tsc2-null ELT3 cells and human tumor cells. Furthermore, we identified hypoxia-inducible factor 1α (HIF-1α) as a mediator transmitting the signal from mTORC1 to PFKFB3. Depletion of PFKFB3 inhibited proliferation and tumorigenicity of Tsc1- or Tsc2-deficient cells. In addition, combination of rapamycin with PFK15, a PFKFB3 inhibitor, exerts a stronger inhibitory effect on cell proliferation of Tsc1- or Tsc2-null 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-1α signaling pathway and co-administration of rapamycin and PFK15 may be a promising strategy for the treatment of TSC tumors as well as other hyperactivated mTORC1-related tumors.
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