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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: BACKGROUND, METHODS, RESULTS. Meshes: Antineoplastic Agents, Apoptosis, Arsenic Trioxide, Arsenicals, Blotting, Western, Carcinoma, Hepatocellular, Caspase 3, Caspase 7, Cell Cycle, Cell Proliferation, Drug Resistance, Neoplasm, Enzyme Activation, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Heat-Shock Proteins, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Lipid Peroxidation, Liver Neoplasms, Membrane Potential, Mitochondrial, Nitric Oxide, Oxides, Oxygen, Reactive Oxygen Species, Tumor Cells, Cultured.
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Is normoxically overexpressed hypoxia inducible factor 1-alpha involved in arsenic trioxide resistance acquisition in hepatocellular carcinoma? Context: The aim of this study was to examine the underlying signaling mechanisms of arsenic trioxide (ATO)-mediated anticancer effects and the responsible biomarker(s) for the acquired resistance in human heptatocellular carcinoma (HCC). The therapeutic effects of ATO were examined using 2 characteristically distinct HCC cell lines, Hep-J5 (overexpressing HIF-1α/GRP78) and SK-Hep-1 (the matched control). ATO-mediated proliferation inhibition, oxidative stress, and apoptosis were analyzed using flowcytometric analysis and western blotting. The role of HIF-1α and GRP78 in HCC resistance to ATO treatment was determined using RNA silencing and inhibitor approaches. SK-Hep-1 cells, lacking both HIF-1α and GRP78 expressions were responsive to ATO-induced apoptosis via an oxidative-nitrosative mechanism. Intracellular glutathione depletion and lipid peroxidation have been identified as the early cascade of events preceding apoptosis via cytochrome c release and the severe drop of mitochondrial membrane potential (MMP). Conversely, Hep-J5 cells, with normoxic coexpression of HIF-1α and GRP78, were resistant to ATO-induced apoptosis. GRP78-silenced Hep-J5 cells remained resistant to ATO treatment. In contrast, ATO resistance in Hep-J5 cells was overcome by the addition of YC-1, a HIF-1α inhibitor.
assistant
HIF-1α was identified as the major positive modifier for ATO resistance acquisition in HCC, and it represents a prime molecular target for overcoming ATO resistance. Final Decision: yes