Sensitization of glycoengineered interferon-β1a-resistant cancer cells by cFLIP inhibition for enhanced anti-cancer therapy

// Tae-Eun Kim 1 , Sungyoul Hong 1 , Kyoung Song 2 , Sang-Ho Park 2, 3 , Young Kee Shin 1 1 College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea 2 Abion Inc., R&D Center, Seoul 08394, Republic of Korea 3 GE Healthcare Korea, R&D Center, Incheon 21988, Republic of Korea Correspondence to: Young Kee Shin, email: ykeeshin@snu.ac.kr Keywords: IFN-β resistance, R27T, cFLIP, sensitization, anti-cancer therapy Received: October 29, 2016      Accepted: December 27, 2016      Published: January 10, 2017 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.