Abstract
TNF-related apoptosis inducing ligand (TRAIL) induces apoptosis through its death receptors (DRs) 4 and/or 5 expressed on the surface of target cells. The selectivity of TRAIL towards cancer cells has promoted clinical evaluation of recombinant human TRAIL (rhTRAIL) and its agonistic antibodies in treating several major human cancers including colon and non-Hodgkin's lymphoma. However, little is known about their ability in killing oral squamous cell carcinoma (OSCC) cells. In this study, we tested the apoptotic responses of a panel of seven human OSCC cell lines (HN31, HN30, HN12, HN6, HN4, Cal27, and OSCC3) to rhTRAIL and monoclonal antibodies against DR4 or DR5. We found that rhTRAIL is a potent inducer of apoptosis in most of the oral cancer cell lines tested both in vitro and in vivo. We also showed that DR5 was expressed on the surface of the tested cell lines which correlated with the cellular susceptibility to apoptosis induced by rhTRAIL and anti-DR5 antibody. By contrast, little or no DR4 was detected on the surface of OSCC3 and HN6 cells rendering cellular resistance to DR4 antibody and a reduced sensitivity to rhTRAIL. Notably, the overall TRAIL sensitivity correlated well with the levels of endogenous active Ras in the cell lines tested. Expression of a constitutively active Ras mutant (RasV12) in OSCC3 cells selectively upregulated surface expression of DR5, but not DR4, and restored TRAIL sensitivity. Our findings could have implications for the use of TRAIL receptor targeted therapies in the treatment of human OSCC tumors particularly the ones harboring constitutively active Ras mutant.
Highlights
Oral squamous cell carcinoma (OSCC) is the most common oral and pharyngeal cancer that affects approximately 500,000 new cases annually worldwide [1, 2]
We found a positive association between TNF-related apoptosis inducing ligand (TRAIL) sensitivity, surface expression of DR4 and DR5, and the levels of activated Ras, with the TRAIL-resistant cell lines OSCC3 being found to be of the lowest levels of surface DR4/DR5 and Ras activity
These results indicate that recombinant human TRAIL (rhTRAIL) is a potent inducer of apoptosis in certain oral squamous cell carcinoma (OSCC) cell lines
Summary
Oral squamous cell carcinoma (OSCC) is the most common oral and pharyngeal cancer that affects approximately 500,000 new cases annually worldwide [1, 2]. Induces apoptosis through its death receptors (DRs) 4 and/ 5 expressed on the surface of target cells. Both receptors are characterized by a cytoplasmic death domain that, upon ligand binding, facilitates the assembly of the death-inducing signaling complex (DISC) involving procaspase-8 or -10 [6, 7]. Preclinical data indicate that recombinant human TRAIL (rhTRAIL) can induce apoptosis in a broad range of human cancer cell lines while sparing most normal cell types [8,9,10,11].
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