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

// Elizabeth Rico-Bautista 1,2 , Wenhong Zhu 3 , Shinichi Kitada 2 , Suthakar Ganapathy 5 , Eric Lau 1,2 , Stan Krajewski 2 , Joel Ramirez 6 , Jason A. Bush 6 , Zhimin Yuan 5,7 , Dieter A. Wolf 1,2,3,4 1 Signal Transduction Program, Sanford-Burnham Medical Research Institute, La Jolla, CA 2 NCI-designated Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 3 Proteomics Facility, Sanford-Burnham Medical Research Institute, La Jolla, CA 4 San Diego Center for Systems Biology, Sanford-Burnham Medical Research Institute, La Jolla, CA 5 Department of Radiation Oncology, University of Texas Health Science Center San Antonio, San Antonio, TX 6 Biology Department, California State University, Fresno, CA 7 Present address: Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA Correspondence: Elizabeth Rico-Bautista, email: // Dieter A. Wolf, email: // Keywords : Prostate cancer, cell cycle arrest, apoptosis, oxidative stress, small molecule inhibitor, mitochondrial function Received : June 26, 2013 Accepted : July 12, 2013 Published : July 14, 2013 Abstract 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.