SMER28 attenuates PI3K/mTOR signaling by direct inhibition of PI3K p110 delta

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Item Type:

Article

Title:

SMER28 attenuates PI3K/mTOR signaling by direct inhibition of PI3K p110 delta

Creators Name:

Kirchenwitz, M. and Stahnke, S. and Prettin, S. and Borowiak, M. and Menke, L. and Sieben, C. and Birchmeier, C. and Rottner, K. and Stradal, T.E.B. and Steffen, A.

Abstract:

SMER28 (Small molecule enhancer of Rapamycin 28) is an autophagy-inducing compound functioning by a hitherto unknown mechanism. Here, we confirm its autophagy-inducing effect by assessing classical autophagy-related parameters. Interestingly, we also discovered several additional effects of SMER28, including growth retardation and reduced G1 to S phase progression. Most strikingly, SMER28 treatment led to a complete arrest of receptor tyrosine kinase signaling, and, consequently, growth factor-induced cell scattering and dorsal ruffle formation. This coincided with a dramatic reduction in phosphorylation patterns of PI3K downstream effectors. Consistently, SMER28 directly inhibited PI3Kδ and to a lesser extent p110γ. The biological relevance of our observations was underscored by SMER28 interfering with InlB-mediated host cell entry of Listeria monocytogenes, which requires signaling through the prominent receptor tyrosine kinase c-Met. This effect was signaling-specific, since entry of unrelated, gram-negative Salmonella Typhimurium was not inhibited. Lastly, in B cell lymphoma cells, which predominantly depend on tonic signaling through PI3Kδ, apoptosis upon SMER28 treatment is profound in comparison to non-hematopoietic cells. This indicates SMER28 as a possible drug candidate for the treatment of diseases that derive from aberrant PI3Kδ activity.

Keywords:

Phosphatidylinositol 3-Kinase (PI 3-Kinase), Mammalian Target of Rapamycin (mTOR), Autophagy, Receptor Tyrosine Kinase, Small Molecule, Actin, Hepatocyte Growth Factor/Scatter Factor (HGF/SF), Platelet-Derived Growth Factor-C (PDGF-C), Cell Proliferation, Cancer Biology

Source:

Cells

ISSN:

2073-4409

Publisher:

MDPI

Volume:

Number:

Page Range:

1648

Date:

16 May 2022