Selectively releasing resistance to TRAIL-mediated apoptosis in cancer cells as therapeutic option for hepatocellular carcinoma

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TRAIL, the TNF-related apoptosis inducing ligand is known for selectively inducing apoptosis in cancer cells while leaving normal cells unharmed and is thus being developed as a promising cancer therapy. However, two issues potentially limiting its clinical applicability have to be addressed: (1) the possibility that TRAIL administration also causes cell death in normal cells under specific pathological conditions and (2) the low response of certain types of cancer cells to TRAIL. In our previous works we have implemented three approaches which could improve TRAIL effectiveness and safety by targeting the well known carcinogenetic pathways of JNK, Src and beta-catenin signalling. We found that inhibition of JNK and Src greatly sensitized liver cancer cell lines but not primary non transformed hepatocytes to TRAIL. This, in a way that effective antitumor TRAIL concentrations could be reduced to levels with negligible toxicity even in normal hepatocytes sensitized to TRAIL. We found that beta-catenin exerts a remarkable antiapoptotic effect in colon carcinoma by driving the expression of osteoprotegerin (OPG) which acts as a soluble decoy receptor for TRAIL. JNK and Src inhibition also caused cell cycle arrest, abolished anchorage independent growth and reduced invasive properties of cancer cells. These findings confirm that the administration of TRAIL is a promising approach to cancer therapy and candidates JNK, Src and OPG as targets for the therapy of tumors. In future experiments we shall aim at investigating how these pathways determine resistance to apoptosis, at assessing the mechanisms of differential sensitization of cancer cells to TRAIL, and will transfer our in vitro studies in vivo.