Endogenous aryl hydrocarbon receptor promotes basal and inducible expression of tumor necrosis factor target genes in MCF-7 cancer cells.

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that upon activation by the toxicant 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) stimulates gene expression and toxicity. AHR is also important for normal mouse physiology and may play a role in cancer progression in the absence of environmental toxicants. The objective of this report was to identify AHR-dependent genes (ADGs) whose expression is regulated by AHR in the absence of toxicants. RNA-Seq analysis revealed that AHR regulated the expression of over 600 genes at an FDR<10% in MCF-7 breast cancer cells upon knockdown with short interfering RNA. Pathway analysis revealed that a significant number of ADGs were components of TCDD and tumor necrosis factor (TNF) pathways. We also demonstrated that siRNA knockdown of AHR modulated TNF induction of MNSOD and cytotoxicity in MCF-7 cells. Collectively, the major new findings of this report are: (1) endogenous AHR promotes the expression of xenobiotic metabolizing enzymes even in the absence of toxicants and drugs, (2) AHR by modulating the basal expression of a large fraction of TNF target genes may prime them for TNF stimulation and (3) AHR is required for TNF induction of MNSOD and the cellular response to cytotoxicity in MCF-7 cells. This latter result provides a potentially new role for AHR in MCF-7 cancer progression as a mediator of TNF and antioxidant responses.

A mitochondria-targeted inhibitor of cytochrome c peroxidase mitigates radiation-induced death.

The risk of radionuclide release in terrorist acts or exposure of healthy tissue during radiotherapy demand potent radioprotectants/radiomitigators. Ionizing radiation induces cell death by initiating the selective peroxidation of cardiolipin in mitochondria by the peroxidase activity of its complex with cytochrome c leading to release of haemoprotein into the cytosol and commitment to the apoptotic program. Here we design and synthesize mitochondria-targeted triphenylphosphonium-conjugated imidazole-substituted oleic and stearic acids that blocked peroxidase activity of cytochrome c/cardiolipin complex by specifically binding to its haem-iron. We show that both compounds inhibit pro-apoptotic oxidative events, suppress cyt c release, prevent cell death, and protect mice against lethal doses of irradiation. Significant radioprotective/radiomitigative effects of imidazole-substituted oleic acid are observed after pretreatment of mice from 1 h before through 24 h after the irradiation.