Upregulation of 6‐phosphofructo‐2‐kinase (PFKFB3) by hyperactivated mammalian target of rapamycin complex 1 is critical for tumor growth in tuberous sclerosis complex

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.

RUNX1/EGFR pathway contributes to STAT3 activation and tumor growth caused by hyperactivated mTORC1

“… 21 , 22 , 23 Using these cell models, we have previously reported that hyperactivated mTORC1 fosters tumor growth by manipulating the expression of multiple glycolytic enzymes, such as PKM2, LDHB, and PFKFB3. 13 , 17 , 24 , 25 RTKs have been shown to be aberrantly expressed in many tumors, including TSC. 26 However, in addition to PDGFRα and PDGFRβ, information on other RTKs that contribute to the development of TSC tumors is limited.…”

Metabolism in tumor microenvironment: Implications for cancer immunotherapy

“… 224 Therefore, there have been several drugs targeted at tumor aerobic glycolysis for cancer treatment, including 2‐Deoxyglucose 225 (the inhibitor of GLUT1 and HK), Dichloroacetate 226 (inducing a shift from glycolysis to OXPHOS), and the inhibitor of phosphofructokinase 1. 227 However, these drugs also significantly inhibit T cell function and promote immunosuppression. 228 Therefore, targeting tumors is important for the application of glycolysis inhibitors in tumor therapy.…”

Canonical and Non-Canonical Roles of PFKFB3 in Brain Tumors

“…PFKFB3 induces mTORC1 activity through expression of pS6K and increases mTORC1 lysosomal translocation independent of AMPK regulation [ 135 ]. Loss of function mutation of tuberous sclerosis complex 1 ( TSC1 ) or 2 ( TSC2 ) leads to accumulation of Rheb GTPase, which subsequently activates mTORC1 [ 144 ]. TSC LOH, as well as the resulting mTORC1 activation, has been extensively documented in astrocytoma, ependymoma, ganglioglioma, oligodendroglioma, and glioblastoma [ 145 ].…”

“…TSC LOH, as well as the resulting mTORC1 activation, has been extensively documented in astrocytoma, ependymoma, ganglioglioma, oligodendroglioma, and glioblastoma [ 145 ]. Activated mTORC1 promotes the expression of HIF-1α, which subsequently increases PFKFB3 transcription and protein expression [ 144 ]. As PFKFB3 can be reciprocally induced by activated mTORC1, PFKFB3 appears to be involved in a vicious cycle of continuous overexpression and oncogenicity in various CNS tumors.…”

“…However, the direct link between TSC LOH and PFKFB3 has not yet been studied in CNS tumors. However, PFKFB3 inhibition has been shown to decrease tumor formation in Tsc1- and Tsc2-null tumors implanted in a mouse model as well as diminishing the cellular proliferation and colony formation in vitro [ 144 ].…”