Blocking autophagy flux promotes interferon-alpha-mediated apoptosis in head and neck squamous cell carcinoma

Wenyi Yang; Chunlan Jiang; Weiya Xia; Houyu Ju; Shufang Jin; Shuli Liu; Liming Zhang; Guoxin Ren; Hailong Ma; Min Ruan; Jingzhou Hu

doi:10.1016/j.canlet.2019.02.052

Blocking autophagy flux promotes interferon-alpha-mediated apoptosis in head and neck squamous cell carcinoma

Cancer Lett. 2019 Jun 1:451:34-47. doi: 10.1016/j.canlet.2019.02.052. Epub 2019 Mar 9.

Authors

Wenyi Yang¹, Chunlan Jiang², Weiya Xia³, Houyu Ju¹, Shufang Jin¹, Shuli Liu¹, Liming Zhang¹, Guoxin Ren¹, Hailong Ma⁴, Min Ruan⁵, Jingzhou Hu⁶

Affiliations

¹ Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China; Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, National Clinical Research Center for Oral Diseases, Shanghai, 200011, China.
² Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, National Clinical Research Center for Oral Diseases, Shanghai, 200011, China; Department of Prosthodontics, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
³ Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
⁴ Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China; Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, National Clinical Research Center for Oral Diseases, Shanghai, 200011, China. Electronic address: mahl21@sjtu.edu.cn.
⁵ Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China; Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, National Clinical Research Center for Oral Diseases, Shanghai, 200011, China. Electronic address: ruanm1740@sh9hospital.org.
⁶ Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China; Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, National Clinical Research Center for Oral Diseases, Shanghai, 200011, China. Electronic address: huyayi@shsmu.edu.cn.

PMID: 30862487
DOI: 10.1016/j.canlet.2019.02.052

Abstract

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 can be activated by IFNα in head and neck squamous cell carcinoma (HNSCC) and serve as a potential target to improve efficacy of IFNα therapy. In this study, we report that IFNα not only exhibits anti-proliferation activity and induces apoptosis, but also activates autophagy in HNSCC cells. Moreover, silencing autophagy-related protein 5 (ATG5) and signal transducer and activator of transcription 1 (STAT1) suppresses autophagy flux. Furthermore, IFNα and autophagy inhibitors (hydroxychloroquine and wortmannin) show clear synergistic effects on inhibiting growth and promoting apoptosis in HNSCC cells and xenograft models. Our findings indicate that IFNα-induced autophagy plays a cytoprotective role and blocking autophagy flux promotes IFNα-mediated apoptosis in HNSCC. These results suggest that the combination of IFNα and autophagy inhibitors represents a novel strategy for HNSCC treatment.

Keywords: Autophagy; Head and neck squamous cell carcinoma; Hydroxychloroquine; Interferon-alpha; Wortmannin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / drug effects*
Autophagy / drug effects*
Autophagy-Related Protein 5 / metabolism
Cell Line, Tumor
Cell Proliferation / drug effects
Head and Neck Neoplasms / pathology*
Heterografts
Humans
Interferon-alpha / pharmacology*
Mice
Mice, Inbred BALB C
STAT1 Transcription Factor / metabolism
Squamous Cell Carcinoma of Head and Neck / pathology*

Substances

ATG5 protein, human
Autophagy-Related Protein 5
Interferon-alpha
STAT1 Transcription Factor
STAT1 protein, human