期刊
ONCOTARGET
卷 8, 期 8, 页码 13957-13970出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.14573
关键词
IFN-beta resistance; R27T; cFLIP; sensitization; anti-cancer therapy
资金
- Bio & Medical Technology Development Program of the National Research Foundation (NRF)-Ministry of Science, ICT & Future Planning [2016M3A9B6903281]
In this study, we examined the molecular mechanism underlying the resistance of cancer cells to R27T, a glycoengineered version of recombinant human interferon (IFN)-beta 1a, 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.
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