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.
Highlights
The imidazolium compound YM155, first discovered as a potent inhibitor of Survivin, effectively kills many carcinomas in preclinical models
We examined the relative potency of YM155 (72 h treatment) in killing various prostate genitourinary cancer cell lines (Table 1, Supplementary Fig. S1A,B), which included the PC-3 AR-negative bone metastatic human prostate cancer (PCa), the AR-negative DU-145 brain metastatic human PCa cell line, the LNCaP androgen-dependent PCa lymph node metastatic cell line, the castration-refractory PCa variant of LNCaP (C4-2), bone metastatic castrate-resistant variant of C4-2 (C4-2B), castrate-resistant PCa cell line derived from a clinically localized tumor (CWR22Rv1), normal human prostate epithelial cells (HPEpiC), immortalized prostate epithelial lines (RWPE-1, RWPE-2), and renal cell carcinoma cell lines (RCC4, 786-O) (Table 1)
Focusing on a direct downstream target of mTOR in complex 1 (mTORC1), we found that pre-treatment of cells with Compound C effectively reversed the dephosphorylation of S6K1 by YM155 (Fig. 8C)
Summary
The imidazolium compound YM155, first discovered as a potent inhibitor of Survivin, effectively kills many carcinomas in preclinical models. Survivin is a unique member of the inhibitor of apoptosis (IAP) family that plays critical roles in cell cycle and cell survival[1]. This IAP is involved in spindle assembly of normal cells[2], and entry of cells into the S phase[3]. Sub-nanomolar concentrations of YM155 inhibit Survivin expression on a broad spectrum of cancer cell lines[7]. These include non-Hodgkin’s lymphoma, castration-refractory prostate cancer (CRPC), ovarian cancer, sarcoma, non-small cell lung carcinoma (NSCLC), breast cancer, leukemia and melanoma. Correspondence and requests for materials should be addressed to D.D.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
