Abstract
In this study, we examined the molecular mechanism underlying the resistance of cancer cells to R27T, a glycoengineered version of recombinant human interferon (IFN)-β1a, and sought to overcome R27T resistance through combination therapy. R27T has been shown to induce anti-proliferation and apoptosis in human OVCAR-3 and MCF-7 cells, but not in HeLa cells. R27T treatment increased caspase-8 activity and the consequent cleavage of caspase-8 and -3 in R27T-sensitive OVCAR-3 cells, but not in R27T-resistant HeLa cells. Conversely, R27T increased the expression of cellular FLICE-like inhibitory protein (cFLIP) in HeLa cells, but not in OVCAR-3 cells. The sensitization of HeLa cells with cFLIP small interfering RNA or 4,5,6,7-tetrabromobenzotriazole (TBB, an inhibitor of casein kinase-2) facilitated R27T-induced caspase activation, and consequently apoptosis. In OVCAR-3-xenografted mice, intraperitoneal administration of R27T showed 2.1-fold higher anti-tumor efficacy than did the control vehicle. The combined administration of R27T and TBB showed the greatest anti-tumor effect in HeLa tumor-bearing mice, reducing the relative tumor volume by 35.7% compared to that in R27T-treated mice. Taken together, our results suggest that R27T has potential as an anti-cancer drug, and combination therapy with cFLIP inhibitors may be an effective strategy for overcoming R27T resistance.
Highlights
Interferon-β (IFN-β) has emerged as a potential anti-cancer drug that can effectively induce cancer growth arrest by decreasing cell proliferation and inducing apoptosis [1]
We found that the treatment of OVCAR-3 and MCF7 cells with R27T increased the proportion of late-stage apoptotic cells to 78.3 and 40.0%, respectively, compared to less than 15% in the untreated cells
We demonstrate the concentrationdependent anti-proliferative and pro-apoptotic effects of R27T in OVCAR-3 and MCF-7 cells via significant induction of IFN and death receptor signaling pathways
Summary
Interferon-β (IFN-β) has emerged as a potential anti-cancer drug that can effectively induce cancer growth arrest by decreasing cell proliferation and inducing apoptosis [1]. The use of IFN-β in anti-cancer therapy has been hampered by its low stability and relatively short circulating half-life (3-5 h in humans) [2]. We developed R27T, a glycoengineered version of recombinant human IFN-β1a. The anti-cancer efficacy of R27T has not yet been fully explored. IFN-β resistance reportedly develops in diverse tumor cells via deregulation of the IFN-β signaling pathway [4,5,6]. We need to explore additional approaches, such as combination therapy, as a means to enhance the therapeutic efficacy of R27T
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