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

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

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., Stahnke, S., Prettin, S., Borowiak, M., Menke, L., Sieben, C., Birchmeier, C., Rottner, K., 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:	11
Number:	10
Page Range:	1648
Date:	16 May 2022
Official Publication:	https://doi.org/10.3390/cells11101648
PubMed:	View item in PubMed

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