The mechanism of apoptosis induction by TGF-β stimuli and its clinical application

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We studied the mechanism of apoptosis induction by TGF-β stimuli for the purpose of applying in the cancer therapy. We established several apoptosis-inducible and -uninducible subclones derived from the single hepatoma cell line, which were partially sensitive to TGF-β stimuli. Our preliminary study using apoptosis-specific cDNA arrays showed that the expression of TNF family members were induced by TGF-β stimuli in the apoptosis-inducible subclones. We studied further the signaling pathways from TGF-β stimuli to apoptosis. After TGF-β stimuli, DNA contents, expression of TNF family, and activation of caspase family were sequentially studied. At first, the G1/G2 arrest was transiently observed, and then the induction of TNF family expression, caspase-8 activation, and apoptosis induction occurred sequentially. We studied the effects of neutralizing antibodies against TNF family members and caspase-8 inhibitor, Z-IETD-FMK against the apoptosis induction, and obtained about 50% inhibition of apoptosis. The NF- κB reporter analysis also showed the activation of NF-κB pathway by TGF-β stimuli. Our studies demonstrated the signaling pathway from TGF-β to apoptosis through TNF family induction and caspase-8 activation. Furhter studies using high-density cDNA array may be required to reveal the whole pathways of apoptosis induction. The activation of NF-κB might be associated with the TGF-β -resistance, but it remains to be determined.