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Induction of autophagy-dependent cell death by the survivin suppressant YM155 in salivary adenoid cystic carcinoma

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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.

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Acknowledgments

This work was supported by grants from National Natural Science Foundation of China (81072203, 81272963) to Z.-J. Sun (81371106) to L. Zhang (81272946) to W.-F. Zhang and (81170977) to Y.-F. Zhao. Fundamental Research Funds for the Central Universities of China (2012304020203) to W. Zhang.

Conflict of interest

No potential conflict of interest was disclosed.

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Authors and Affiliations

  1. 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

    Yu-Fan Wang, Wei Zhang, Ke-Fei He, Bing Liu, Lu Zhang, Wen-Feng Zhang, Yi-Fang Zhao & Zhi-Jun Sun

  2. Functional Genomics Section, Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, 20892, USA

    Ashok B. Kulkarni

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  1. Yu-Fan Wang
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  2. Wei Zhang
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  4. Bing Liu
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  5. Lu Zhang
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  8. Yi-Fang Zhao
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Corresponding authors

Correspondence to Yi-Fang Zhao or Zhi-Jun Sun.

Additional information

Y.-F. Wang and W. Zhang contributed equally to this study.

Electronic supplementary material

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10495_2013_960_MOESM1_ESM.ppt

Supplementary Fig. 1 (PPT 216 kb) Correlation of expression level of survivin with CDK4/CyclinD1/p-RbS780 in human salivary gland ACC tissues

10495_2013_960_MOESM2_ESM.ppt

Supplementary Fig. 2 (PPT 159 kb) YM155 induce apoptotic cell death in human ACC-M cell line. a Cell viability of ACC-M was measured using an MTT assay after treated with YM155 for 24 h. The viability ratio is normalized by the ratio of the optical density value obtained from the YM155-treated sample divided by that of control group. b Cell death detection ELISA analysis of cell proliferation inhibited by YM155 in dose-dependent manner in ACC-M was detected. **P < 0.01; ***P < 0.001 as compared with the control group. One-way ANOVA with post-Dunnett analysis was used

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Wang, YF., Zhang, W., He, KF. et al. Induction of autophagy-dependent cell death by the survivin suppressant YM155 in salivary adenoid cystic carcinoma. Apoptosis 19, 748–758 (2014). https://doi.org/10.1007/s10495-013-0960-1

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  • DOI: https://doi.org/10.1007/s10495-013-0960-1

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