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.

Targeting of Survivin Pathways by YM155 Inhibits Cell Death and Invasion in Oral Squamous Cell Carcinoma Cells

“…This small imidazolium compound was initially identified from a pharmacological screen based on BIRC5 promoter inhibition and described as a first in class "Survivin suppressant". YM155 has been demonstrated to exert antitumor activity, to suppress Survivin expression and to induce tumor cell apoptosis and inhibit cell metastasis, in various human cancer models [13,14,[16][17][18]. Our current data show that YM155 not only inhibits cell growth but also induces apoptotic cell death of survivin-rich expressed SCC9 cells, a finding similar to those observed in Melanoma [25], renal Cell Carcinoma [26], multiple myeloma [27] and head neck squamous cell carcinoma [28,29].…”

“…YM155 has been demonstrated to exert antitumor activity, to suppress Survivin expression and to induce tumor cell apoptosis and inhibit cell metastasis, in various human cancer models [13,14,[16][17][18]. Our current data show that YM155 not only inhibits cell growth but also induces apoptotic cell death of survivin-rich expressed SCC9 cells, a finding similar to those observed in Melanoma [25], renal Cell Carcinoma [26], multiple myeloma [27] and head neck squamous cell carcinoma [28,29]. However, YM155 treatment did not affect growth and apoptosis of poor-survivin expressed SCC25 cells, suggesting YM155 could be a target for the treatment of survivin-rich expressed OSSC.…”

“…Its primary functions comprise inhibiting apoptosis and regulating mitosis, which are associated with metastasis and carcinogenesis [8][9][10][11]. YM155, a novel small-molecule surviving suppressant, selectively suppresses surviving expression, resulting in the induction of apoptosis and invasion inhibition in various malignancies [12][13][14][15][16]. Furthermore, treatment with YM155 did not affecting normal tissues [13].…”

Rapamycin enhances the anti-angiogenesis and anti-proliferation ability of YM155 in oral squamous cell carcinoma

“…13,30 YM155, a potent survivin inhibitor, has been used as an anti-cancer agent in many tumors, 9 which can suppress the proliferation of the tumor cells and induce tumor cells death. [31][32][33] We examined that YM155 significantly inhibited the proliferation ability of OSCC cell lines in a dose-dependent manner.…”

“…[10][11][12] In OSCC, YM155 can suppress its growth by promoting apoptosis and autophagy and inhibiting proliferation. 13,14 Rapamycin, an immunosuppressive agent, was used widely to avoid immunological rejection in the organ transplantation. 15,16 Recently, it was revealed that rapamycin could suppress tumor growth through anti-angiogenesis and promote cell death by inhibiting the mammalian target of rapamycin (mTOR) pathway.…”