title: Induction of autophagy-dependent cell death by the survivin suppressant YM155 in salivary adenoid cystic carcinoma.
abstract: Adenoid cystic carcinoma (ACC) is one of the most common malignancies of the major and minor salivary glands. However, the molecular mechanism underlying the aggressive growth of human salivary ACC remains unclear. In the present study, we showed that survivin, which belongs to the family of inhibitors of apoptosis, is closely related to the high expression of CDK4 and cyclin D1 in human ACC specimens. By employing the small-molecule drug YM155, we found that the inhibition of survivin in ACC cells caused significant cell death and induced autophagy. Chloroquine, an autophagy inhibitor, prevented cell death induced by YM155, suggesting YM155-induced autophagy contributed to the cell death effects in ACC cells. More importantly, evidence obtained from a xenograft model using ACC-2 cells proved the occurrence of YM155-induced autophagy and cell death in vivo was correlated with the suppression of Erk1/2 and S6 activation as well as increased TFEB nuclear translocation. Taken together, our results indicate YM155 is a novel inducer of autophagy-dependent cell death and possesses therapeutic potential in ACC.
authors.affiliation: The State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory of Oral Biomedicine Ministry of Education, Department of Oral and Maxillofacial-Head and Neck Oncology, School and Hospital of Stomatology, Wuhan University, Wuhan, 430079, China.
authors.forename: Yu-Fan
authors.initials: YF
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Ke-Fei
authors.initials: KF
authors.lastname: He
authors.forename: Bing
authors.initials: B
authors.lastname: Liu
authors.forename: Lu
authors.initials: L
authors.lastname: Zhang
authors.forename: Wen-Feng
authors.initials: WF
authors.lastname: Zhang
authors.forename: Ashok B
authors.initials: AB
authors.lastname: Kulkarni
authors.forename: Yi-Fang
authors.initials: YF
authors.lastname: Zhao
authors.forename: Zhi-Jun
authors.initials: ZJ
authors.lastname: Sun
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D003528:Carcinoma, Adenoid Cystic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D064593:Heterografts; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009062:Mouth Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D009285:Naphthoquinones / Q000494:pharmacology*; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D012469:Salivary Glands / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D000077022:Survivin
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D009285:Naphthoquinones; D000077022:Survivin; C523798:sepantronium