Inhibition of mTOR complex 2 restrains tumor angiogenesis in multiple myeloma

Oncotarget
Aurelia LamanuzziRoberto Ria

Abstract

The mammalian Target of Rapamycin (mTOR) is an intracellular serine/threonine kinase that mediates intracellular metabolism, cell survival and actin rearrangement. mTOR is made of two independent complexes, mTORC1 and mTORC2, activated by the scaffold proteins RAPTOR and RICTOR, respectively. The activation of mTORC1 triggers protein synthesis and autophagy inhibition, while mTORC2 activation promotes progression, survival, actin reorganization, and drug resistance through AKT hyper-phosphorylation on Ser473. Due to the mTOR pivotal role in the survival of tumor cells, we evaluated its activation in endothelial cells (ECs) from 20 patients with monoclonal gammopathy of undetermined significance (MGUS) and 47 patients with multiple myeloma (MM), and its involvement in angiogenesis. MM-ECs showed a significantly higher expression of mTOR and RICTOR than MGUS-ECs. These data were supported by the higher activation of mTORC2 downstream effectors, suggesting a major role of mTORC2 in the angiogenic switch to MM. Specific inhibition of mTOR activity through siRNA targeting RICTOR and dual mTOR inhibitor PP242 reduced the MM-ECs angiogenic functions, including cell migration, chemotaxis, adhesion, invasion, in vitro angiogenesis on Ma...Continue Reading

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Citations

May 3, 2019·Journal of Molecular Histology·Dan HuangXingmei Feng
Jul 22, 2019·Journal of Clinical Medicine·Antonio Giovanni SolimandoHermann Einsele
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Jul 22, 2021·Cancer Biology & Therapy·Fabio SallustioAnna Gallone

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Methods Mentioned

BETA
transfection
zymography
ELISA
flow cytometry
scraping
FACS

Software Mentioned

EVOS
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