Early Cellular Responses of Prostate Carcinoma Cells to Sepantronium Bromide (YM155) Involve Suppression of mTORC1 by AMPK

Abstract The imidazolium compound YM155, first discovered as a potent inhibitor of Survivin, effectively kills many carcinomas in preclinical models. However, the upstream signaling mechanism triggered by YM155 remains unclear. Here we studied early signaling responses in vitro in prostate and renal...

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Autores principales: David Danielpour, Zhaofeng Gao, Patrick M. Zmina, Eswar Shankar, Benjamin C. Shultes, Raul Jobava, Scott M. Welford, Maria Hatzoglou
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Publicado: Nature Portfolio 2019
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spelling oai:doaj.org-article:413a98d689b543009470d4c60ab64d4b2021-12-02T15:08:32ZEarly Cellular Responses of Prostate Carcinoma Cells to Sepantronium Bromide (YM155) Involve Suppression of mTORC1 by AMPK10.1038/s41598-019-47573-y2045-2322https://doaj.org/article/413a98d689b543009470d4c60ab64d4b2019-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-019-47573-yhttps://doaj.org/toc/2045-2322Abstract The imidazolium compound YM155, first discovered as a potent inhibitor of Survivin, effectively kills many carcinomas in preclinical models. However, the upstream signaling mechanism triggered by YM155 remains unclear. Here we studied early signaling responses in vitro in prostate and renal cancer cell lines in a dose-dependent manner. We found that YM155 rapidly activates the retinoblastoma protein, correlating with the loss of expression of all three Cyclin Ds. Using Western blot, various selective chemical inhibitors and q-PCR, we show that YM155-mediated decrease in protein levels of Cyclin Ds, Survivin and Mcl-1 is independent of transcription or proteasomal control mechanisms. Moreover, we provide the first evidence that YM155 changes the phosphorylation status of known mTOR-target proteins involved in translational control, namely ribosomal protein S6 (rS6) and 4E-BP1. Our data support that YM155 achieves this by blocking mTORC1 via the phosphorylation of Raptor at S792 through activated AMPKα (T172). Furthermore, we also used a polysome profile, supporting that YM155 markedly suppresses cap-dependent translation of mRNAs which include Survivin, Cyclin D1 and Mcl-1. We provide the first evidence that YM155 functions as a potent activator of AMPKα, a robust suppressor of mTORC1 and an attenuator of global protein synthesis.David DanielpourZhaofeng GaoPatrick M. ZminaEswar ShankarBenjamin C. ShultesRaul JobavaScott M. WelfordMaria HatzoglouNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 9, Iss 1, Pp 1-17 (2019)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
David Danielpour
Zhaofeng Gao
Patrick M. Zmina
Eswar Shankar
Benjamin C. Shultes
Raul Jobava
Scott M. Welford
Maria Hatzoglou
Early Cellular Responses of Prostate Carcinoma Cells to Sepantronium Bromide (YM155) Involve Suppression of mTORC1 by AMPK
description Abstract The imidazolium compound YM155, first discovered as a potent inhibitor of Survivin, effectively kills many carcinomas in preclinical models. However, the upstream signaling mechanism triggered by YM155 remains unclear. Here we studied early signaling responses in vitro in prostate and renal cancer cell lines in a dose-dependent manner. We found that YM155 rapidly activates the retinoblastoma protein, correlating with the loss of expression of all three Cyclin Ds. Using Western blot, various selective chemical inhibitors and q-PCR, we show that YM155-mediated decrease in protein levels of Cyclin Ds, Survivin and Mcl-1 is independent of transcription or proteasomal control mechanisms. Moreover, we provide the first evidence that YM155 changes the phosphorylation status of known mTOR-target proteins involved in translational control, namely ribosomal protein S6 (rS6) and 4E-BP1. Our data support that YM155 achieves this by blocking mTORC1 via the phosphorylation of Raptor at S792 through activated AMPKα (T172). Furthermore, we also used a polysome profile, supporting that YM155 markedly suppresses cap-dependent translation of mRNAs which include Survivin, Cyclin D1 and Mcl-1. We provide the first evidence that YM155 functions as a potent activator of AMPKα, a robust suppressor of mTORC1 and an attenuator of global protein synthesis.
format article
author David Danielpour
Zhaofeng Gao
Patrick M. Zmina
Eswar Shankar
Benjamin C. Shultes
Raul Jobava
Scott M. Welford
Maria Hatzoglou
author_facet David Danielpour
Zhaofeng Gao
Patrick M. Zmina
Eswar Shankar
Benjamin C. Shultes
Raul Jobava
Scott M. Welford
Maria Hatzoglou
author_sort David Danielpour
title Early Cellular Responses of Prostate Carcinoma Cells to Sepantronium Bromide (YM155) Involve Suppression of mTORC1 by AMPK
title_short Early Cellular Responses of Prostate Carcinoma Cells to Sepantronium Bromide (YM155) Involve Suppression of mTORC1 by AMPK
title_full Early Cellular Responses of Prostate Carcinoma Cells to Sepantronium Bromide (YM155) Involve Suppression of mTORC1 by AMPK
title_fullStr Early Cellular Responses of Prostate Carcinoma Cells to Sepantronium Bromide (YM155) Involve Suppression of mTORC1 by AMPK
title_full_unstemmed Early Cellular Responses of Prostate Carcinoma Cells to Sepantronium Bromide (YM155) Involve Suppression of mTORC1 by AMPK
title_sort early cellular responses of prostate carcinoma cells to sepantronium bromide (ym155) involve suppression of mtorc1 by ampk
publisher Nature Portfolio
publishDate 2019
url https://doaj.org/article/413a98d689b543009470d4c60ab64d4b
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