Unknown,Transcriptomics,Genomics,Proteomics

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Small molecule-induced bioenergetic reprogramming 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, such as cyclin A, CDK4 and SKP2 while upregulating cyclin-dependent kinase inhibitors p27 and p21, resulting in G1 arrest and inhibition of colony formation in soft agar. However, the mechanism of SMIP004-induced cancer cell selective apoptosis remained unknown. We used profiling to unravel a SMIP004-induced pro-apoptotic pathway, which initiates with bioenergetic reprogramming at the level of mitochondria. SMIP004 causes downregulation of aerobic glycolysis, rapid upregulation of components of the mitochondrial electron transport chain, and oxidative stress. The latter, in turn, elicits cell cycle arrest by rapidly targeting cyclin D1 for proteasomal degradation, drives transcriptional downregulation of the androgen receptor, and activates pro-apoptotic signaling through the unfolded protein response and MAPK activation. Finally SMIP004 was found to potently inhibit the growth of prostate and breast cancer xenografts in mice. There are two biological replicates SMIP004Rep1 and SMIP004Rep2 and two technical replicates for each biological replicates (SMIP004 Rep1_1 and SMIP004 Rep1_2). Total RNA from cells treated with 40 uM SMIP004 for 24 h, vehicle or positive controls (Roscovitine, 20uM, Campthotecin 500 nMM, Bortezomib 50 nM) was obtained using the RNeasy Mini Kit. The drug treated and control samples were compared.

ORGANISM(S): Homo sapiens

SUBMITTER: Roy Williams

PROVIDER: E-GEOD-48056 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:The identification of recurrent somatic mutations in genes encoding epigenetic enzymes, coupled with biochemical studies demonstrating aberrant recruitment of epigenetic enzymes such as histone deacetylases (HDACs) and histone methyltransferases (HMTs) to promoter regions through association with oncogenic fusion proteins such as PML-RARM-NM-1 and AML1-ETO has provided a strong rationale for the development compounds that target the epigenome for the treatment of cancer. HDAC inhibitors (HDACi) are potent inducers of tumor cell apoptosis but it remains unclear why tumor cells are selectively sensitive to HDACi-induced cell death. Herein we assessed the biological and molecular responses of normal and transformed cells to the FDA-approved HDACi vorinostat. Both HDACi selectively killed cells of diverse tissue origin that had been transformed through the serial introduction of different oncogenes. Time course microarray expression profiling revealed that normal and transformed cells transcriptionally responded to vorinostat treatment. Over 4200 genes responded differently to vorinostat in normal and transformed cells and gene ontology and pathway analyses identified a tumor-cell-selective pro-apoptotic gene-expression signature that consisted of BCL2 family genes. In particular, HDACi induced tumor cell-selective upregulation of the pro-apoptotic gene BMF and downregulation of the pro-survival gene BCL2A1 encoding BFL-1. Maintenance of BFL-1 levels in transformed cells through forced expression conferred vorinostat resistance indicating that specific and selective engagement of the intrinsic apoptosis pathways underlies the tumor cell-selective apoptotic activities of these agents. The ability of HDACi to affect the growth and survival of tumor cells whilst leaving normal cells relatively unharmed is fundamental to their successful clinical application. This study provides new insight into the transcriptional effects of HDACi in human donor-matched normal and transformed cells, and identifies molecules and pathways that could underpin the tumor-selective cytotoxic activity of these compounds. Whole genome expression profiling was performed for vorinostat-treated samples and control samples (DMSO vehicle control). Fourteen samples were included in this study. Each sample has three biological replicates, making forty-two arrays in total.

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Small molecule-induced bioenergetic reprogramming directs prostate cancer inhibition via UPR signaling

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