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 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.

The role of survivin in the progression of pancreatic ductal adenocarcinoma (PDAC) and a novel survivin-targeted therapeutic for PDAC

“…Polysome profiles were generated in renal and prostate cancer cell lines following YM155 treatment which showed that YM155 substantially suppresses cap-dependent translation of mRNAs that include survivin [31]. Before any noticeable changes in mRNA transcripts, this experiment showed a significant suppression in translation as early as 4 hours after the start of YM155 treatment.…”

Molecular Mechanism of Autophagy: Its Role in the Therapy of Alzheimer’s Disease

“…Upon cellular stresses, AMPK interacts with and phosphorylates ULK1 on Ser 317 and Ser 777, leading to the dissociation of the ULK1-mTORC1 complex, translocation of ULK to the pre-autophagosomal membrane and eventually induction of autophagy [ 79 ]. Alternatively, AMPK may inhibit mTORC1 activation by directly phosphorylating raptor on two conserved serine residues (Ser722 and Ser792) [ 81 ]. Lately, several new findings have suggested that ULk1 provides potential negative feedback for AMPK activity by phosphorylating all three subunits of AMPK (AMPK-α, β and -γ) [ 25 , 82 ].…”

YM155-Adapted Cancer Cell Lines Reveal Drug-Induced Heterogeneity and Enable the Identification of Biomarker Candidates for the Acquired Resistance Setting

“…Sepantronium bromide (YM155) was introduced as an anti-cancer drug candidate that inhibits expression of the BIRC5 gene, which encodes the protein survivin [1]. In the meantime, YM155 has been suggested to exert additional and/or alternative mechanisms of anticancer actions, including induction of DNA damage, inhibition of NFκB signaling, induction of death receptor 5 expression, and/or suppression of MCL-1, XIAP, cIAP-1/2, BCL-2, BCL-XL, FLIP, EGFR, and/or mTORC [2][3][4][5][6][7][8][9][10][11][12][13].…”