SMER28 Attenuates PI3K/mTOR Signaling by Direct Inhibition of PI3K p110 Delta

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 PI3K delta and to a lesser extent p110 gamma. 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 PI3K delta, 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 PI3K delta activity.

Automated summary

SMER28 is a compound that induces autophagy through an unknown mechanism. It also has additional effects such as growth retardation and inhibition of receptor tyrosine kinase signaling, which leads to the inhibition of cell scattering and dorsal ruffle formation. Furthermore, SMER28 interferes with the entry of Listeria monocytogenes by inhibiting the signaling of the prominent receptor tyrosine kinase c-Met. In B cell lymphoma cells, which rely on PI3Kδ signaling, SMER28 induces apoptosis.