Abstract
TNF-related apoptosis inducing ligand (TRAIL) induces apoptosis by engaging its death receptors (DRs) 4 and/or 5 on targeted cells. Clinical attempts to stimulate this apoptotic pathway for cancer therapy, including the use of recombinant human TRAIL (rhTRAIL) or receptor agonistic antibodies, have been underway for over a decade. Unfortunately, these agents have only shown limited therapeutic effects due largely to tumor resistance arising from mechanisms yet to be defined. Here we show that intermediate filament proteins, keratin 8 and keratin 18 (K8/K18), negatively regulate TRAIL induced apoptosis. K8/K18 protein levels are consistently higher in TRAIL-resistant cells compared to TRAIL-sensitive cells in a panel of breast cancer cell lines. Blockade of K8 increased expression of DR5 on the surface of targeted cells and sensitized the cells to TRAIL-induced apoptosis. Conversely, ectopic expression of K8/K18 downregulated DR5 protein expression. K8/K18 appears to negatively regulate apoptosis signaling via DR5 in breast cancer cells. Our findings warrant additional studies to determine if K8/K18 could be a predictor of tumor resistance to DR5-targeted therapies.
Highlights
Death receptors (DRs) 4 and 5 are cell surface receptors that transmit apoptotic signals initiated by their cognate ligand TNF-related apoptosis inducing ligand (TRAIL)
Our findings warrant additional studies to determine if keratin 8 and keratin 18 (K8/K18) could be a predictor of tumor resistance to DR5-targeted therapies
Keratin 8/18 expression correlates with TRAIL resistance in breast cancer cells
Summary
Death receptors (DRs) 4 and 5 are cell surface receptors that transmit apoptotic signals initiated by their cognate ligand TNF-related apoptosis inducing ligand (TRAIL). A body of preclinical evidence showed that recombinant human TRAIL preferentially induced apoptosis in cancer cells without harming most normal cells [2, 3] This unique selectivity led to multiple clinical programs aimed at evaluating the antitumor activities of recombinant human TRAIL and agonistic antibodies against DR4 or DR5 [4]. Recent efforts were shifted to the development of second generation DR5-targeted agents with expected improvement in therapeutic effects [5, 6] In this context, a better understanding of tumor resistance mechanisms helps identify biomarkers to predict the likelihood of tumor response to DR5-targeted therapies in individual patients. This information can aid in guiding the selection of combination drugs to achieve better cancer treatment outcomes
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