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Small Molecule-Induced Mitochondrial Disruption Directs Prostate Cancer Inhibition via Unfolded Protein Response Signaling

We previously identified SMIP004 (N-(4-butyl-2-methyl-phenyl) acetamide) as a novel inducer of cancer-cell selective apoptosis of human prostate cancer cells. SMIP004 decreased the levels of positive cell cycle regulators, upregulated cyclin-dependent kinase inhibitors, and resulted in G1 arrest, in...

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Autores principales: Rico-Bautista, Elizabeth, Zhu, Wenhong, Kitada, Shinichi, Ganapathy, Suthakar, Lau, Eric, Krajewski, Stan, Ramirez, Joel, Bush, Jason A., Yuan, Zhimin, Wolf, Dieter A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3787152/
https://www.ncbi.nlm.nih.gov/pubmed/23902736
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author Rico-Bautista, Elizabeth
Zhu, Wenhong
Kitada, Shinichi
Ganapathy, Suthakar
Lau, Eric
Krajewski, Stan
Ramirez, Joel
Bush, Jason A.
Yuan, Zhimin
Wolf, Dieter A.
author_facet Rico-Bautista, Elizabeth
Zhu, Wenhong
Kitada, Shinichi
Ganapathy, Suthakar
Lau, Eric
Krajewski, Stan
Ramirez, Joel
Bush, Jason A.
Yuan, Zhimin
Wolf, Dieter A.
author_sort Rico-Bautista, Elizabeth
collection PubMed
description We previously identified SMIP004 (N-(4-butyl-2-methyl-phenyl) acetamide) as a novel inducer of cancer-cell selective apoptosis of human prostate cancer cells. SMIP004 decreased the levels of positive cell cycle regulators, upregulated cyclin-dependent kinase inhibitors, and resulted in G1 arrest, inhibition of colony formation in soft agar, and cell death. However, the mechanism of SMIP004-induced cancer cell selective apoptosis remained unknown. Here, we used chemical genomic and proteomic profiling to unravel a SMIP004-induced pro-apoptotic pathway, which initiates with disruption of mitochondrial respiration leading to oxidative stress. This, in turn, activates two pathways, one eliciting cell cycle arrest by rapidly targeting cyclin D1 for proteasomal degradation and driving the transcriptional downregulation of the androgen receptor, and a second pathway that activates pro-apoptotic signaling through MAPK activation downstream of the unfolded protein response (UPR). SMIP004 potently inhibits the growth of prostate and breast cancer xenografts in mice. Our data suggest that SMIP004, by inducing mitochondrial ROS formation, targets specific sensitivities of prostate cancer cells to redox and bioenergetic imbalances that can be exploited in cancer therapy.
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spelling pubmed-37871522013-10-01 Small Molecule-Induced Mitochondrial Disruption Directs Prostate Cancer Inhibition via Unfolded Protein Response Signaling Rico-Bautista, Elizabeth Zhu, Wenhong Kitada, Shinichi Ganapathy, Suthakar Lau, Eric Krajewski, Stan Ramirez, Joel Bush, Jason A. Yuan, Zhimin Wolf, Dieter A. Oncotarget Research Paper We previously identified SMIP004 (N-(4-butyl-2-methyl-phenyl) acetamide) as a novel inducer of cancer-cell selective apoptosis of human prostate cancer cells. SMIP004 decreased the levels of positive cell cycle regulators, upregulated cyclin-dependent kinase inhibitors, and resulted in G1 arrest, inhibition of colony formation in soft agar, and cell death. However, the mechanism of SMIP004-induced cancer cell selective apoptosis remained unknown. Here, we used chemical genomic and proteomic profiling to unravel a SMIP004-induced pro-apoptotic pathway, which initiates with disruption of mitochondrial respiration leading to oxidative stress. This, in turn, activates two pathways, one eliciting cell cycle arrest by rapidly targeting cyclin D1 for proteasomal degradation and driving the transcriptional downregulation of the androgen receptor, and a second pathway that activates pro-apoptotic signaling through MAPK activation downstream of the unfolded protein response (UPR). SMIP004 potently inhibits the growth of prostate and breast cancer xenografts in mice. Our data suggest that SMIP004, by inducing mitochondrial ROS formation, targets specific sensitivities of prostate cancer cells to redox and bioenergetic imbalances that can be exploited in cancer therapy. Impact Journals LLC 2013-07-14 /pmc/articles/PMC3787152/ /pubmed/23902736 Text en Copyright: © 2013 Rico-Bautista et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
spellingShingle Research Paper
Rico-Bautista, Elizabeth
Zhu, Wenhong
Kitada, Shinichi
Ganapathy, Suthakar
Lau, Eric
Krajewski, Stan
Ramirez, Joel
Bush, Jason A.
Yuan, Zhimin
Wolf, Dieter A.
Small Molecule-Induced Mitochondrial Disruption Directs Prostate Cancer Inhibition via Unfolded Protein Response Signaling
title Small Molecule-Induced Mitochondrial Disruption Directs Prostate Cancer Inhibition via Unfolded Protein Response Signaling
title_full Small Molecule-Induced Mitochondrial Disruption Directs Prostate Cancer Inhibition via Unfolded Protein Response Signaling
title_fullStr Small Molecule-Induced Mitochondrial Disruption Directs Prostate Cancer Inhibition via Unfolded Protein Response Signaling
title_full_unstemmed Small Molecule-Induced Mitochondrial Disruption Directs Prostate Cancer Inhibition via Unfolded Protein Response Signaling
title_short Small Molecule-Induced Mitochondrial Disruption Directs Prostate Cancer Inhibition via Unfolded Protein Response Signaling
title_sort small molecule-induced mitochondrial disruption directs prostate cancer inhibition via unfolded protein response signaling
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3787152/
https://www.ncbi.nlm.nih.gov/pubmed/23902736
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