Clinical immunology : the official journal of the Clinical Immunology Society
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Many tumors are resistant to Fas ligand (FasL)-induced apoptosis. This study examined the role of tumor-derived TNF-alpha, via an autocrine/paracrine loop, in the regulation of tumor-cell resistance to FasL-induced apoptosis. We have reported that Fas expression and sensitivity to FasL is negatively regulated by the transcription repressor factor Yin Yang 1 (YY1). ⋯ The direct role of YY1 expression in the regulation of PC-3 resistance to CH-11-induced apoptosis was shown in cells transfected with siRNA YY1 whereby such cells exhibited upregulation of Fas expression and were sensitized to CH-11-induced apoptosis. These findings demonstrate that the TNF-alpha autocrine-paracrine loop is involved in the constitutive activation of the transcription factors NF-kappaB and YY1 in the tumor cells and this loop leads to inhibition of Fas expression and resistance to FasL-induced apoptosis. Further, these findings identify new targets such as TNF-alpha, NF-kappaB and YY1, whose inhibition can reverse tumor cell resistance to FasL-mediated apoptosis.