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

David Danielpour, Zhaofeng Gao, Patrick M. Zmina, Eswar Shankar, Benjamin C. Shultes, Raul Jobava, Scott Welford, Maria Hatzoglou

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number11541
JournalScientific reports
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2019

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AMP-Activated Protein Kinases
Cyclins
Prostate
TOR Serine-Threonine Kinases
Ribosomal Protein S6
Phosphorylation
Raptors
Carcinoma
Retinoblastoma Protein
Polyribosomes
Kidney Neoplasms
Cyclin D1
Protein Biosynthesis
Prostatic Neoplasms
Proteins
Western Blotting
Cell Line
Polymerase Chain Reaction
mechanistic target of rapamycin complex 1
YM 155

ASJC Scopus subject areas

  • General

Cite this

Danielpour, D., Gao, Z., Zmina, P. M., Shankar, E., Shultes, B. C., Jobava, R., ... Hatzoglou, M. (2019). Early Cellular Responses of Prostate Carcinoma Cells to Sepantronium Bromide (YM155) Involve Suppression of mTORC1 by AMPK. Scientific reports, 9(1), [11541]. https://doi.org/10.1038/s41598-019-47573-y

Early Cellular Responses of Prostate Carcinoma Cells to Sepantronium Bromide (YM155) Involve Suppression of mTORC1 by AMPK. / Danielpour, David; Gao, Zhaofeng; Zmina, Patrick M.; Shankar, Eswar; Shultes, Benjamin C.; Jobava, Raul; Welford, Scott; Hatzoglou, Maria.

In: Scientific reports, Vol. 9, No. 1, 11541, 01.12.2019.

Research output: Contribution to journalArticle

Danielpour, David ; Gao, Zhaofeng ; Zmina, Patrick M. ; Shankar, Eswar ; Shultes, Benjamin C. ; Jobava, Raul ; Welford, Scott ; Hatzoglou, Maria. / Early Cellular Responses of Prostate Carcinoma Cells to Sepantronium Bromide (YM155) Involve Suppression of mTORC1 by AMPK. In: Scientific reports. 2019 ; Vol. 9, No. 1.
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