IDENTIFICATION OF A NOVEL TRAIL SIGNALLING MECHANISM IN THE NASOPHARYNGEAL CARCINOMA MODEL

Abstract

Nasopharyngeal carcinoma (NPC) is a cancer originating in the nasopharynx. It is vastly more common in Southern China, Southeast Asia, Japan, and the Middle East/North Africa than elsewhere, with viral, dietary and genetic factors implicated in its causation. The treatment for NPC includes radiotherapy and chemotherapy. However, one of the major drawbacks of the treatment is the non-tumour specific killing. Thus alternative therapeutic that could target cancer cells would be desirable. TNF-family related apoptosis inducing ligand (TRAIL) has shown promise as a target-specific agent against tumour cells. The heightened interest in evaluating the potential use of TRAIL in the clinical settings stems from observations that TRAIL receptors, DR4 and DR5, are selectively expressed on tumour cells. To that end, TRAIL is under investigation for their potential to be a NPC therapeutic. We recently demonstrated that TRAIL is able to induce apoptosis in two NPC cell lines, HK-1 and C666-1. Serendipitously, we found that there is a non-classical early activation of effector caspase-3 in the NPC model. We link this to the presence of caspases-3 in the cell surface membrane lipid raft. This allows caspsase-3 to be in close proximity to the death-inducing signaling complex (DISC) in the lipid rafts even before death trigger. As a result, upon trigger, caspases-3 can be activated much earlier.