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Hyperactivated mTORC1 downregulation of FOXO3a/PDGFRα/AKT cascade restrains tuberous sclerosis complex-associated
Li Wang1, Zhaofei Ni1, Yujie Liu2
1Department of Biochemistry and Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China.
Abstract:
Hyperactivation of mammalian target of rapamycin complex 1 (mTORC1), caused by loss-of-function mutations in either the TSC1 or TSC2 gene, leads to the development of tuberous sclerosis complex (TSC), a benign tumor syndrome with multiple affected organs. mTORC1-mediated inhibition of AKT constrains the tumor progression of TSC, but the exact mechanisms remain unclear. Herein we showed that loss of TSC1 or TSC2 downregulation of platelet-derived growth factor receptor α (PDGFRα) expression was mediated by mTORC1. Moreover, mTORC1 inhibited PDGFRα expression via suppression of forkhead box O3a (FOXO3a)-mediated PDGFRα gene transcription. In addition, ectopic expression of PDGFRα promoted AKT activation and enhanced proliferation and tumorigenic capacity of Tsc1- or Tsc2-null mouse embryonic fibroblasts (MEFs), and vice versa. Most importantly, rapamycin in combination with AG1295, a PDGFR inhibitor, significantly inhibited growth of TSC1/TSC2 complex-deficient cells in vitro and in vivo. Therefore, downregulated FOXO3a/PDGFRα/AKT pathway exerts a protective effect against hyperactivated mTORC1-induced tumorigenesis caused by loss of TSC1/TSC2 complex, and the combination of rapamycin and AG1295 may be a new effective strategy for TSC-associated tumors treatment.
Insights
Loss of TSC1/TSC2 causes tuberous sclerosis complex (TSC) by activating mTORC1. Downregulation of FOXO3a/PDGFRα/AKT signaling protects against TSC tumors. Combination therapy shows promise for TSC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Tuberous sclerosis complex (TSC) arises from TSC1/TSC2 gene mutations, leading to mTORC1 hyperactivation and benign tumors.
- The precise mechanisms by which mTORC1 constrains TSC tumor progression are not fully understood.
Purpose of the Study:
- To elucidate the role of mTORC1 in regulating platelet-derived growth factor receptor α (PDGFRα) expression in TSC.
- To investigate the FOXO3a/PDGFRα/AKT pathway in TSC tumorigenesis.
- To evaluate the therapeutic potential of combining mTORC1 and PDGFR inhibitors.
Main Methods:
- Investigated PDGFRα expression in TSC1/TSC2-deficient cells.
- Analyzed mTORC1's regulation of FOXO3a-mediated PDGFRα transcription.
- Assessed the impact of PDGFRα expression on AKT activation and cell proliferation.
- Evaluated the efficacy of combined rapamycin and AG1295 treatment in vitro and in vivo.
Main Results:
- Loss of TSC1 or TSC2 leads to mTORC1-mediated downregulation of PDGFRα expression.
- mTORC1 suppresses FOXO3a-driven PDGFRα gene transcription.
- Ectopic PDGFRα expression promotes AKT activation and tumorigenesis in TSC-deficient cells.
- Combined rapamycin and AG1295 significantly inhibits TSC1/TSC2 complex-deficient cell growth.
Conclusions:
- The downregulated FOXO3a/PDGFRα/AKT pathway offers protection against mTORC1-driven tumorigenesis in TSC.
- Combined inhibition of mTORC1 and PDGFR represents a potential therapeutic strategy for TSC-associated tumors.
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