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mTORC1 is a critical mediator of oncogenic Semaphorin3A signaling

Daisuke Yamada1, Kohichi Kawahara1, Takehiko Maeda1

  • 1Department of Pharmacology, Faculty of Pharmacy, Niigata University of Pharmacy and Applied Life Sciences, 265-1 Higashijima, Akiha-ku, Niigata-shi, Niigata-ken 956-8603, Japan.

Biochemical and Biophysical Research Communications
|June 2, 2016
PubMed

Insights

Semaphorin3A (Sema3A) signaling promotes tumor growth by enhancing aerobic glycolysis via the mTORC1 pathway. This study reveals Sema3A

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Metabolism

Background:

  • Aberrant signaling pathways contribute to tumor development and metastasis.
  • The precise mechanisms and signaling molecules driving oncogenesis remain incompletely understood.

Purpose of the Study:

  • To investigate the role of Semaphorin3A (Sema3A) signaling in regulating the oncogenic activity within mouse Lewis lung carcinoma cells (LLCs).
  • To elucidate the molecular mechanisms by which Sema3A influences cancer cell metabolism and proliferation.

Main Methods:

  • Utilized shRNA to knock down Sema3A expression in LLCs.
  • Assessed apoptosis, cell proliferation, mammalian target of rapamycin complex 1 (mTORC1) levels, and glycolytic activity.
  • Examined cellular responses to oligomycin (oxidative phosphorylation inhibitor) and glucose starvation.
  • Administered recombinant SEMA3A and rapamycin (mTORC1 inhibitor) to evaluate rescue and counteraction effects.

Main Results:

  • Sema3A knockdown reduced LLC proliferation and decreased both mTORC1 levels and glycolytic activity.
  • Sema3A knockdown increased sensitivity to oxidative phosphorylation inhibition but conferred resistance to glucose starvation.
  • Recombinant SEMA3A restored proliferation and glycolysis, an effect blocked by mTORC1 inhibition.

Conclusions:

  • Sema3A signaling promotes oncogenesis by driving a metabolic shift from oxidative phosphorylation to aerobic glycolysis, mediated by mTORC1.
  • Targeting the Sema3A-mTORC1-glycolysis axis may offer therapeutic strategies for lung carcinoma.
Keywords:
GlycolysisLung cancerSemaphorin3AmTOR signaling

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