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,...
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MDPI AG
2022-05-01
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| author | Marco Kirchenwitz Stephanie Stahnke Silvia Prettin Malgorzata Borowiak Laura Menke Christian Sieben Carmen Birchmeier Klemens Rottner Theresia E. B. Stradal Anika Steffen |
| author_facet | Marco Kirchenwitz Stephanie Stahnke Silvia Prettin Malgorzata Borowiak Laura Menke Christian Sieben Carmen Birchmeier Klemens Rottner Theresia E. B. Stradal Anika Steffen |
| author_sort | Marco Kirchenwitz |
| collection | DOAJ |
| description | 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 <i>Listeria monocytogenes</i>, which requires signaling through the prominent receptor tyrosine kinase c-Met. This effect was signaling-specific, since entry of unrelated, gram-negative <i>Salmonella</i> 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. |
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| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T03:10:24Z |
| publishDate | 2022-05-01 |
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| record_format | Article |
| series | Cells |
| spelling | doaj.art-2a8ee43ec6084ff5a40865674077a6a22023-11-23T10:27:40ZengMDPI AGCells2073-44092022-05-011110164810.3390/cells11101648SMER28 Attenuates PI3K/mTOR Signaling by Direct Inhibition of PI3K p110 DeltaMarco Kirchenwitz0Stephanie Stahnke1Silvia Prettin2Malgorzata Borowiak3Laura Menke4Christian Sieben5Carmen Birchmeier6Klemens Rottner7Theresia E. B. Stradal8Anika Steffen9Department of Cell Biology, Helmholtz Centre for Infection Research, 38124 Braunschweig, GermanyDepartment of Cell Biology, Helmholtz Centre for Infection Research, 38124 Braunschweig, GermanyDepartment of Cell Biology, Helmholtz Centre for Infection Research, 38124 Braunschweig, GermanyDevelopmental Biology/Signal Transduction, Max Delbrueck Center for Molecular Medicine, 13125 Berlin, GermanyNanoscale Infection Biology Group, Helmholtz Centre for Infection Research, 38124 Braunschweig, GermanyNanoscale Infection Biology Group, Helmholtz Centre for Infection Research, 38124 Braunschweig, GermanyDevelopmental Biology/Signal Transduction, Max Delbrueck Center for Molecular Medicine, 13125 Berlin, GermanyDepartment of Cell Biology, Helmholtz Centre for Infection Research, 38124 Braunschweig, GermanyDepartment of Cell Biology, Helmholtz Centre for Infection Research, 38124 Braunschweig, GermanyDepartment of Cell Biology, Helmholtz Centre for Infection Research, 38124 Braunschweig, GermanySMER28 (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 <i>Listeria monocytogenes</i>, which requires signaling through the prominent receptor tyrosine kinase c-Met. This effect was signaling-specific, since entry of unrelated, gram-negative <i>Salmonella</i> 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.https://www.mdpi.com/2073-4409/11/10/1648phosphatidylinositol 3-kinase (PI 3-kinase)mammalian target of rapamycin (mTOR)autophagyreceptor tyrosine kinasesmall moleculeactin |
| spellingShingle | Marco Kirchenwitz Stephanie Stahnke Silvia Prettin Malgorzata Borowiak Laura Menke Christian Sieben Carmen Birchmeier Klemens Rottner Theresia E. B. Stradal Anika Steffen SMER28 Attenuates PI3K/mTOR Signaling by Direct Inhibition of PI3K p110 Delta Cells phosphatidylinositol 3-kinase (PI 3-kinase) mammalian target of rapamycin (mTOR) autophagy receptor tyrosine kinase small molecule actin |
| title | SMER28 Attenuates PI3K/mTOR Signaling by Direct Inhibition of PI3K p110 Delta |
| title_full | SMER28 Attenuates PI3K/mTOR Signaling by Direct Inhibition of PI3K p110 Delta |
| title_fullStr | SMER28 Attenuates PI3K/mTOR Signaling by Direct Inhibition of PI3K p110 Delta |
| title_full_unstemmed | SMER28 Attenuates PI3K/mTOR Signaling by Direct Inhibition of PI3K p110 Delta |
| title_short | SMER28 Attenuates PI3K/mTOR Signaling by Direct Inhibition of PI3K p110 Delta |
| title_sort | smer28 attenuates pi3k mtor signaling by direct inhibition of pi3k p110 delta |
| topic | phosphatidylinositol 3-kinase (PI 3-kinase) mammalian target of rapamycin (mTOR) autophagy receptor tyrosine kinase small molecule actin |
| url | https://www.mdpi.com/2073-4409/11/10/1648 |
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