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

Sci Rep. 2019 Aug 8;9(1):11541. doi: 10.1038/s41598-019-47573-y.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinase Kinases
  • Adaptor Proteins, Signal Transducing / genetics
  • Apoptosis / drug effects
  • Carcinoma / drug therapy*
  • Carcinoma / genetics
  • Carcinoma / pathology
  • Cell Cycle Proteins / genetics
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cyclin D / genetics
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Imidazoles / pharmacology*
  • Male
  • Mechanistic Target of Rapamycin Complex 1 / genetics
  • Naphthoquinones / pharmacology*
  • Prostate / drug effects
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / pathology
  • Protein Kinases / genetics*
  • Signal Transduction / drug effects
  • Survivin / genetics

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Cyclin D
  • EIF4EBP1 protein, human
  • Imidazoles
  • Naphthoquinones
  • Survivin
  • Protein Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • AMP-Activated Protein Kinase Kinases
  • sepantronium