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Molecular mechanisms of apoptosis and autophagy elicited by combined treatment with oridonin and cetuximab in laryngeal squamous cell carcinoma

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Combined oridonin (ORI), a natural and safe kaurene diterpenoid isolated from Rabdosia rubescens, and cetuximab (Cet), an anti-EGFR monoclonal antibody, have been reported to exert synergistic anti-tumor effects against laryngeal squamous cell carcinoma (LSCC) both in vitro and in vivo by our group. In the present study, we further found that ORI/Cet treatment not only resulted in apoptosis but also induced autophagy. AMPK/mTOR signaling pathway was found to be involved in the activation of autophagy in ORI/Cet-treated LSCC cells, which is independent of p53 status. Additionally, chromatin immunoprecipitation (ChIP) assay showed that ORI/Cet significantly increased the binding NF-κB family member p65 with the promotor of BECN 1, and p65-mediated up-regulation of BECN 1 caused by ORI/Cet is coupled to increased autophagy. On the other hand, we demonstrated that either Beclin 1 SiRNA or autophagy inhibitors could increase ORI/Cet induced-apoptosis, indicating that autophagy induced by combination of the two agents plays a cytoprotective role. Interestingly, 48 h after the combined treatment, autophagy began to decrease but apoptosis was significantly elevated. Our findings suggest that autophagy might be strongly associated with the antitumor efficacy of ORI/Cet, which may be beneficial to the clinical application of ORI/Cet in LSCC treatment.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant Numbers: 81373797 and 81102855). This study is also supported by the China Postdoctoral Science Special Foundation (Grant Number: 2014T70224) and the China Postdoctoral Science Foundation (Grant Number: 2013M541192).

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  1. Shijie Cao and Yiyuan Huang have contributed equally to this work.

Authors and Affiliations

  1. School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, 312 Anshanxi Road, Tianjin, 300193, People’s Republic of China

    Yiyuan Huang, Qiang Zhang & Ning Kang

  2. Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, People’s Republic of China

    Shijie Cao, Yiyuan Huang & Yan Zhu

  3. School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, People’s Republic of China

    Fangjin Lu & Feng Qiu

  4. School of Pharmacy, University of Health and Allied Sciences, Ho, PMB 31, Ghana

    Paul Owusu Donkor

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  1. Shijie Cao
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Cao, S., Huang, Y., Zhang, Q. et al. Molecular mechanisms of apoptosis and autophagy elicited by combined treatment with oridonin and cetuximab in laryngeal squamous cell carcinoma. Apoptosis 24, 33–45 (2019). https://doi.org/10.1007/s10495-018-1497-0

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