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IRS\u20104 expression increases dramatically after partial hepatectomy and plays an important role in HepG2 hepatoblastoma cell line proliferation\/differentiation. In human hepatocarcinoma, IRS\u20104 overexpression has been associated with tumor development. Herein, we describe the mechanism whereby IRS\u20104 depletion induced by RNA interference (siRNA) sensitizes HepG2 cells to treatment with actinomycin D (Act D) and combined treatment with Act D plus tumor necrosis factor\u2010\u03b1 (TNF\u2010\u03b1). Similar results have been obtained in HuH 7 and Chang cell lines. Act D therapy drove the cells to a mitochondrial\u2010dependent apoptotic program involving cytochrome <jats:italic>c<\/jats:italic> release, caspase 3 activation, PARP fragmentation and DNA laddering. TNF\u2010\u03b1 amplifies the effect of Act D on HepG2 cell apoptosis increasing c\u2010jun N\u2010terminal kinase (JNK) activity, I\u03baB\u2010\u03b1 proteolysis and glutathione depletion. IRS\u20104 depleted cells that were treated with Act D showed an increase in cytochrome <jats:italic>c<\/jats:italic> release and procaspase 3 and PARP proteolysis with respect to control cells. The mechanism involved in IRS\u20104 action is independent of Akt, I\u03baB kinase and JNK. IRS\u20104 down regulation, however, decreased \u03b3\u2010glutamylcysteine synthetase content and cell glutathione level in the presence of Act D plus TNF\u2010\u03b1. These results suggest that IRS\u20104 protects HepG2 cells from oxidative stress induced by drug treatment. J. Cell. Biochem. 108: 1292\u20131301, 2009. \u00a9 2009 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/jcb.22359","type":"journal-article","created":{"date-parts":[[2009,9,30]],"date-time":"2009-09-30T17:48:52Z","timestamp":1254332932000},"page":"1292-1301","source":"Crossref","is-referenced-by-count":15,"title":["RNAi\u2010mediated silencing of insulin receptor substrate\u20104 enhances actinomycin D\u2010 and tumor necrosis factor\u2010\u03b1\u2010induced cell death in hepatocarcinoma cancer cell lines"],"prefix":"10.1002","volume":"108","author":[{"given":"Eva 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