Abstract
TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis through death receptors (DRs) 4 and/or 5 expressed on the surface of target cells. We have previously shown that deficiency of DR4 and DR5 on the surface membrane is a critical mechanism of cancer cell resistance to the recombinant human TRAIL and its receptor agonistic antibodies, which are being evaluated clinically for treating cancers. In certain cancer cells, DR4 and DR5 were found to be mislocalized in intracellular compartments yet to be characterized. Here, we report a novel role of autophagy in the regulation of dynamics of TRAIL death receptors. We first assessed basal levels of autophagosomes in a panel of 11 breast cancer cell lines using complementary approaches (LC3 immunoblotting, RFP-LC3 fluorescence microscopy, and electron microscopy). We found high levels of basal autophagosomes in TRAIL resistant breast cancer cell lines (e.g. BT474 and AU565) and relevant mouse xenograft models under nutrition-rich conditions. Notably, DR4 and DR5 co-localized with LC3-II in the autophagosomes of TRAIL-resistant cells. Disruption of basal autophagosomes successfully restored the surface expression of the death receptors which was accompanied by sensitization of TRAIL-resistant cells to TRAIL induced apoptosis. By contrast, TRAIL-sensitive cell lines (MDA-MB-231) are characterized by high levels of surface DR4/DR5 and an absence of basal autophagosomes. Inhibition of lysosomal activity induced an accumulation of autophagosomes and a decrease in surface DR4 and DR5, and the cells became less sensitive to TRAIL-induced apoptosis. These findings demonstrate a novel role for the basal autophagosomes in the regulation of TRAIL death receptors. Further studies are warranted to explore the possibility of using autophagosome markers such as LC3-II/LC3-I ratios for prediction of tumor resistance to TRAIL related therapies. The results also provide a rationale for future non-clinical and clinical studies testing TRAIL agonists in combination with agents that directly inhibit autophagosome assembly.
Highlights
TNF-related apoptosis-inducing ligand (TRAIL) is best known for its ability to induce apoptosis in cancer cells without causing damage to most normal cells [1,2,3]
Overcoming tumor resistance is the key to success of development of TRAIL receptor targeted therapies for cancer treatment
We have previously shown an aberrant expression of TRAIL death receptors in certain cancer cell lines in which these receptors are mainly localized in intracellular compartments such as nucleus and others yet to be characterized [29, 30]
Summary
TNF-related apoptosis-inducing ligand (TRAIL) is best known for its ability to induce apoptosis in cancer cells without causing damage to most normal cells [1,2,3]. Oncotarget 2013; 4: 1349-1364 trials to evaluate the antitumor potential of recombinant human TRAIL (rhTRAIL) and its receptor-specific agonistic antibodies [4,5,6]. These therapies act through death receptor (DRs) 4 and/or 5 expressed on the surface of target cells, thereby inducing the assembly of the death inducing signaling complex (DISC) and activation of a caspase cascade. It is critical to fully understand the mechanisms underlying TRAIL resistance and to apply the information into the design and selection of combinational drugs to overcome cancer drug resistance towards a better clinical outcome of cancer treatment
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