TRAIL resistance mediated by constitutively active autophagy

Monday, October 24, 2011 — Poster Session I
Noon – 2:00 p.m.	Natcher Conference Center	FDA/CBER	CANCER-6

Authors

• X Di
• Y Zhang
• L Rivera Rosado
• J Chen
• B Zhang

Abstract

Tumor necrosis (TNF)-related apoptosis-inducing ligand (TRAIL) has been shown to selectively induce apoptosis in cancer cells over most normal cells. This unique property of TRAIL has promoted multiple clinical trials with recombinant human TRAIL (rhTRAIL) and monoclonal antibodies against its death receptors (DRs) 4 and/or 5 for treating various malignancies. However, their therapeutic potential is limited by the development of resistance in cancer cells. Our previous studies have identified deficiencies in apoptosis pathways that contribute to TRAIL resistance. In this study, we investigate whether autophagy plays a role in TRAIL resistance. We found that LC3 II, a molecule marker of autophagy, was expressed at significantly higher levels in TRAIL-resistant cell lines than TRAIL-sensitive lines. The higher expression of LC3 II was associated with an accumulation of endogenous autophagosomes in TRAIL-resistant cells. Inhibition of autophagy by pharmacological inhibitor or RNAi sensitized the cells to TRAIL-induced apoptosis. We also provide cellular and biochemical data that further demonstrate a cytoprotective role of autophagy in some breast cancer cells. These results warrant additional studies to evaluate autophagy regulators as biomarkers of TRAIL resistance and their potential as therapeutic targets for overcoming tumor resistance to TRAIL related therapies

back to top