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Endothelial Cell mTOR Complex-2 Regulates Sprouting Angiogenesis.

Maikel A Farhan1, Katia Carmine-Simmen2, John D Lewis2

  • 1Department of Medicine, University of Alberta, Edmonton, Canada.

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Summary
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Targeting mammalian target of rapamycin complex 2 (mTORC2) inhibits tumor angiogenesis by affecting endothelial cell migration and cytoskeletal remodeling, independent of Akt1 signaling. This offers new therapeutic strategies for cancer treatment.

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Area of Science:

  • Oncology
  • Cell Biology
  • Molecular Biology

Background:

  • Tumor angiogenesis, driven by vascular endothelial growth factor (VEGF), is a key target for cancer therapy.
  • Resistance to anti-angiogenic drugs limits clinical efficacy, necessitating exploration of alternative pathways.
  • Mammalian target of rapamycin (mTOR) pathway, particularly mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), plays a role in tumor growth and angiogenesis.

Purpose of the Study:

  • To elucidate the specific role of mTORC2 in endothelial cells (ECs) and tumor angiogenesis.
  • To compare the functions of mTORC2 with Akt1 and mTORC1 in ECs.
  • To investigate the mechanisms by which mTORC2 regulates angiogenesis.

Main Methods:

  • Utilized pharmacological inhibitors and RNA interference in human endothelial cells.
  • Assessed angiogenic sprouting, EC migration, cytoskeleton organization, and matrix adhesion signaling.
  • Studied the effects of mTORC1 inhibition, mTORC1/2 dual inhibition, and selective mTORC2 inactivation.

Main Results:

  • Sustained mTORC1 inhibition led to increased mTORC2-dependent Akt1 activation, rendering ECs resistant to apoptosis and hyper-responsive to angiogenesis.
  • Dual mTORC1/2 inhibition or selective mTORC2 inactivation suppressed angiogenesis stimulated by renal cell carcinoma (RCC) cells and VEGF.
  • mTORC2 inactivation significantly reduced EC migration, actin polymerization, focal adhesion formation, and focal adhesion kinase activation, independent of Akt1.

Conclusions:

  • Endothelial mTORC2 is a critical regulator of angiogenesis.
  • mTORC2 controls angiogenesis through focal adhesion kinase activity, matrix adhesion, and cytoskeletal remodeling, independently of the Akt/mTORC1 pathway.
  • Targeting endothelial mTORC2 presents a promising strategy to overcome resistance to current anti-angiogenic therapies.