title: Targeting non-canonical autophagy overcomes erlotinib resistance in tongue cancer.
abstract: Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) frequently occurs in many human cancers and hampers their therapeutic use. A large body of evidence has demonstrated the pro-survival role of autophagy in many human cancers. However, whether autophagy is involved in the induction of erlotinib resistance in tongue squamous cell carcinoma (TSCC) remains unknown. In this report, we found that autophagy prior to or induced by erlotinib treatment plays an important role in erlotinib resistance in tongue cancer cells. Using LC3 transfection, we observed that autophagy is upregulated and further induced when treated with erlotinib. Moreover, we found that autophagy plays a cytoprotective role by MTT analysis of the cell viability in TSCCs when treated with rapamycin or hydroxychloroquine (HCQ) in combination with erlotinib. However, 3-methyladenine (3-MA) did not influence the autophagy. Then, through siRNA technology and WB, we found that erlotinib-induced autophagy is mediated by ATG5 but not Beclin1. Also, knockdown of ATG5 significantly decreased the erlotinib resistance and knockdown of Beclin1 did not affect the sensitivity to erlotinib in TSCCs. Taken together, this indicates the critical role of non-canonical autophagy in erlotinib resistance in TSCCs.
authors.affiliation: School of Stomatology, Liaoning Medical University, 3-40 Songpo Road, Jinzhou, 121000, Liaoning, People's Republic of China.|School of Stomatology Shandong University, Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Shandong University, Jinan, 250012, China.
authors.forename: Keqiang
authors.initials: K
authors.lastname: Huang
authors.affiliation: School of Stomatology Shandong University, Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Shandong University, Jinan, 250012, China. liudongxu@sdu.edu.cn.
authors.forename: Dongxu
authors.initials: D
authors.lastname: Liu
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D000071187:Autophagy-Related Protein 5 / Q000378:metabolism; D000071186:Beclin-1 / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology*; D006801:Humans; D006886:Hydroxychloroquine / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D014062:Tongue Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D034741:RNA, Small Interfering; D006886:Hydroxychloroquine; C025946:3-methyladenine; D000069347:Erlotinib Hydrochloride; D000225:Adenine; D020123:Sirolimus
keywords: ATG5; Autophagy; Chemotherapeutic resistance; Erlotinib