The Molecular Mechanisms Of Blocking Autophagy Flux Promoting Interferon-alpha-mediated Apoptosis In Head And Neck Squamous Cell Carcinoma

Objectives:Despite multiple antitumor activities,interferon-alpha（IFNα） therapy alone is less effective in solid tumors.Autophagy has been reported to play a key role in tumor chemoresistance.Therefore,it is meaningful to explore whether autophagy could be activated by IFNαin head and neck squamous cell carcinoma（HNSCC）and serve as a potential target to improve the therapeutic efficacy of IFNαtherapy.Methods:The interactions between IFNα,wortmannin,and hydroxychloroquine were evaluated in vitro in HNSCC cells.The synergistic effect of IFNα（20 000 IU per day,s.c.）,hydroxychloroquine(60 mg kg^-1 per day,i.p.)and wortmannin(0.7 mg kg^-1per day,s.c.)was further confirmed in vivo using HNSCC xenografts in nude mice. The activation of autophagy induced by IFNa and its mechanism were detected in vitro and in vivo.Results:IFNαnot only exhibits anti-proliferation activity and induces apoptosis,but also activates autophagy in HNSCC cells.In addition,silencing autophagy-related protein 5（ATG5）and signal transducer and activator of transcription 1（STAT1） expression suppresses autophagy flux.Moreover,IFNαand autophagy inhibitors（hydroxychloroquine and wortmannin）show clear synergistic effects on inhibiting growth and promoting apoptosis in HNSCC cells and xenograft models.Conclusions:IFNα-induced autophagy plays a cytoprotective role and blocking autophagy flux promotes IFNα-mediated apoptosis in HNSCC.The combination of IFNαand autophagy inhibitors represents a novel strategy for HNSCC treatment.