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mTORC1-mediated downregulation of COX2 restrains tumor growth caused by TSC2 deficiency

Hongwu Li1,2, Fuquan Jin3,4, Keguo Jiang3,5

  • 1Department of Otorhinolaryngology, Head & Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China.

Oncotarget
|April 15, 2016
PubMed

Insights

Tuberous sclerosis complex (TSC) tumors involve hyperactive mTORC1 signaling. Loss of TSC2 reduces cyclooxygenase 2 (COX2), promoting tumor growth. Combining rapamycin and celecoxib may treat TSC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Tuberous sclerosis complex (TSC) is a genetic disorder characterized by benign tumor formation in multiple organs.
  • Hyperactivation of the mammalian target of rapamycin complex 1 (mTORC1) pathway is a key driver of TSC-associated tumorigenesis.
  • Loss-of-function mutations in TSC1 or TSC2 genes underlie TSC pathogenesis.

Purpose of the Study:

  • To investigate the role of cyclooxygenase 2 (COX2) as a downstream target of mTORC1 in TSC.
  • To explore the therapeutic potential of targeting the mTORC1/COX2 pathway in TSC.

Main Methods:

  • Analysis of Tsc2-null mouse embryonic fibroblasts (MEFs) and Tsc2-null ELT3 cells.
  • Assessment of COX2 expression and its regulation by the mTORC1/STAT3 signaling pathway.
  • Evaluation of the effects of COX2 modulation and combination therapy (rapamycin and celecoxib) on cell proliferation and tumor growth.

Main Results:

  • Loss of TSC2 led to decreased COX2 expression via mTORC1/STAT3 activation.
  • COX2 overexpression promoted proliferation and growth of Tsc2-null cells, partly through IL-6 upregulation.
  • COX2 knockdown inhibited proliferation in control cells.
  • Combined treatment with rapamycin and celecoxib significantly inhibited Tsc2-deficient cell growth.

Conclusions:

  • Downregulation of COX2 offers protection against mTORC1-mediated tumorigenesis in TSC2-deficient cells.
  • Combination therapy with rapamycin and celecoxib shows promise as a novel therapeutic strategy for TSC.
Keywords:
COX2IL-6STAT3TSCmTOR

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