Combined oridonin,a natural and safe kaurene diterpenoid isolated from Rabdosia rubescens,and cetuximab,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 oridonin/cetuximab 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 oridonin/cetuximab-treated LSCC cells,which is independent of p53 status.Additionally,chromatin immunoprecipitation(ChIP)assay showed that oridonin/cetuximab significantly increased the binding NF-kB family member p65 with the promotor of BECN 1,and p65-mediated up-regulation of BECN1 caused by oridonin/cetuximab is coupled to increased autophagy.On the other hand,we demonstrated that either Beclin 1 SiRNA or autophagy inhibitors could increase oridonin/cetuximab induced-apoptosis,indicating that autophagy induced by combination of the two agents plays a cytoprotective role.Interestingly,48 hours after the combined treatment,autophagy began to decrease but apoptosis was significantly elevated,suggesting a switch from autophagy to apoptosis for long term treatment with oridonin/cetuximab.Our findings suggest that autophagy might be strongly associated with the antitumor efficacy of oridonin/cetuximab,which may be beneficial to the clinical application of oridonin/cetuximab in LSCC treatment.