title: Small molecule-induced mitochondrial disruption directs prostate cancer inhibition via UPR signaling.
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.
authors.affiliation: Signal Transduction Program, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA. erico@sanfordburnham.org
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Rico-Bautista
authors.forename: Wenhong
authors.initials: W
authors.lastname: Zhu
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kitada
authors.forename: Suthakar
authors.initials: S
authors.lastname: Ganapathy
authors.forename: Eric
authors.initials: E
authors.lastname: Lau
authors.forename: Stan
authors.initials: S
authors.lastname: Krajewski
authors.forename: Joel
authors.initials: J
authors.lastname: Ramirez
authors.forename: Jason A
authors.initials: JA
authors.lastname: Bush
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Yuan
authors.forename: Dieter A
authors.initials: DA
authors.lastname: Wolf
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011897:Random Allocation; D015398:Signal Transduction / Q000187:drug effects; D025801:Ubiquitin / Q000378:metabolism; D056811:Unfolded Protein Response / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000081:Acetamides; D025801:Ubiquitin; D019938:Cyclin D1; D046988:Proteasome Endopeptidase Complex
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