Role of Extracellular Matrix Proteins in Conferring Cancer Cell Resistance to Tumor Necrosis Factor

Abstract

In a recent study we have shown that both the induction of cellular protein-tyrosine phosphorylation and the secretion of a novel extracellular matrix TNF-resistance triggering (TRT) protein are involved in the TGF-ß1 protection of murine L929 fibrosarcoma cells against the cytotoxic effect of TNF-α in the presence of ActD. TRT activates cellular protein kinases, thereby maintaining relatively high levels of phosphorylation and sustaining the TNF-resistance in L929 cells. In this study it is determined that TNF-resistant cervical carcinoma cells, ME-180 and HeLa, constitutively express TRT, and that TGF-ß1 further upregulates TRT expression. Unlike the TRT secreted from TGF-ß-treated L929 cells, ME-180-derived TRT blocks the cytotoxic action of TNF-α in the presence of ActD and the antiproliferative effects of TNF a alone. HeLa-derived TRT inhibits the cytotoxic but not growth inhibitory effect of TNF-α. These observations suggest that two types of TRT molecules are secreted in the extracellular matrix by ME-180. Conceivably, TRT provides a novel self-defense mechanism for cancer cells to evade TNF killing and immune attack.