Dual induction of apoptotic and autophagic cell death by targeting survivin in head neck squamous cell carcinoma.

L Zhang,Y-F Wang,Y-F Zhao,W-F Zhang,W Zhang,Z-J Sun,A B Kulkarni,B Liu

doi:10.1038/cddis.2015.139

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.

Highlights

head neck squamous cell cancer (HNSCC) is combined surgery, radiotherapy, chemotherapy and biotherapy; the 5-year survival rate is still o50%, and the long-term survival rate has only marginally improved.[4,5,6] As an important hallmark of head and neck cancer, apoptosis resistance restricts the efficacy of traditional therapies.[7]
The cell viability was estimated by trypan blue exclusion (TBE) assays, suggesting at the concentration of 10 nM, YM155 caused signficant cell death
The increase in the population of Annexin V − /PI+ necrotic cells indicated that a high YM155 dose might exert potential cytotoxicity against HNSCC (Figure 1c)

Summary

Introduction

HNSCC is combined surgery, radiotherapy, chemotherapy and biotherapy; the 5-year survival rate is still o50%, and the long-term survival rate has only marginally improved.[4,5,6] As an important hallmark of head and neck cancer, apoptosis resistance restricts the efficacy of traditional therapies.[7]. Recent studies including ours have demonstrated YM155 triggered autophagy in cancer cells.[15,16,17] Macroautophagy or autophagy is considered to be another type of programmed cell death wherein proteins are degraded by autophagosomes and lysosomes.[18] Autophagy has an important role in tumorigenesis.[19] Autophagy shares several regulatory systems and common pathways with apoptosis; autophagy is closely linked with apoptosis. YM155 may induce the apoptosis and affect the autophagy in HNSCC

Methods

Results

Conclusion