title: Dual induction of apoptotic and autophagic cell death by targeting survivin in head neck squamous cell carcinoma.
abstract: Survivin is ubiquitously expressed in patients with head neck squamous cell carcinoma (HNSCC) and is associated with poor survival and chemotherapy resistance. Sepantronium bromide (YM155) is a selective survivin suppressant that exhibits potent antitumor activities by inducing apoptosis and autophagy in various types of cancer. However, the curative effects and underlying mechanisms of YM155 in HNSCC remain unclear. This study showed that survivin overexpression positively correlated with p-S6, p-Rb and LAMP2 but negatively correlated with the autophagic marker LC3 in human HNSCC tissues. In vitro studies revealed that YM155 triggered apoptosis of HNSCC cells in mitochondria and death receptor-dependent manner. The treatment also significantly enhanced autophagy by upregulating Beclin1, which led to cell death. YM155 not only downregulated the expression of survivin but also remarkably suppressed the activation of the mTOR signaling pathway in vitro and in vivo. YM155 displayed potent antitumor activities in both CAL27 xenograft and transgenic HNSCC mice models by delaying tumor onset and suppressing tumor growth. Furthermore, YM155 combined with docetaxel promoted tumor regression better than either treatment alone without causing considerable body weight loss in the HNSCC xenograft models. Overall, targeting survivin by YM155 can benefit HNSCC therapy by increasing apoptotic and autophagic cell death, and suppressing prosurvival pathways.
authors.affiliation: The State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.affiliation: The State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China.
authors.forename: W
authors.initials: W
authors.lastname: Zhang
authors.affiliation: The State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China.
authors.forename: Y-F
authors.initials: YF
authors.lastname: Wang
authors.affiliation: Department of Oral and Maxillofacial-Head and Neck Oncology, School and Hospital of Stomatology, Wuhan University, Wuhan, China.
authors.forename: B
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Oral and Maxillofacial-Head and Neck Oncology, School and Hospital of Stomatology, Wuhan University, Wuhan, China.
authors.forename: W-F
authors.initials: WF
authors.lastname: Zhang
authors.affiliation: 1] The State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China [2] Department of Oral and Maxillofacial-Head and Neck Oncology, School and Hospital of Stomatology, Wuhan University, Wuhan, China.
authors.forename: Y-F
authors.initials: YF
authors.lastname: Zhao
authors.affiliation: Functional Genomics Section, Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
authors.forename: A B
authors.initials: AB
authors.lastname: Kulkarni
authors.affiliation: 1] The State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China [2] Department of Oral and Maxillofacial-Head and Neck Oncology, School and Hospital of Stomatology, Wuhan University, Wuhan, China.
authors.forename: Z-J
authors.initials: ZJ
authors.lastname: Sun
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis; D001343:Autophagy / Q000502:physiology*; D000071186:Beclin-1; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D020287:In Situ Nick-End Labeling; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D052119:Lysosomal-Associated Membrane Protein 2 / Q000378:metabolism; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000473:pathology; D009285:Naphthoquinones / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000077195:Squamous Cell Carcinoma of Head and Neck; D000077022:Survivin; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D013629:Tamoxifen / Q000494:pharmacology; D043823:Taxoids / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; C107489:BIRC5 protein, human; D000071186:Beclin-1; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; C497811:LAMP2 protein, human; D052119:Lysosomal-Associated Membrane Protein 2; C477012:MAP1LC3A protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D009285:Naphthoquinones; D016160:Retinoblastoma Protein; D000077022:Survivin; D043823:Taxoids; D013629:Tamoxifen; D000077143:Docetaxel; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; C523798:sepantronium