Survivin inhibitor YM155 induces mitochondrial dysfunction, autophagy, DNA damage and apoptosis in Bcl‐xL silenced glioma cell lines

Abstract

Because the anti-apoptotic protein Bcl-xL is overexpressed in glioma, one might expect that inhibiting or silencing this gene would promote tumor cell killing. However, our studies have shown that this approach has limited independent activity, but may tip the balance in favor of apoptosis induction in response to other therapeutic interventions. To address this issue, we performed a pharmacological screen using a panel of signaling inhibitors and chemotherapeutic agents in Bcl-xL silenced cells. Although limited apoptosis induction was observed with a series of inhibitors for receptor tyrosine kinases, PKC inhibitors, Src family members, JAK/STAT, histone deacetylase, the PI3K/Akt/mTOR pathway, MAP kinase, CDK, heat shock proteins, proteasomal processing, and various conventional chemotherapeutic agents, we observed a dramatic potentiation of apoptosis in Bcl-xL silenced cells with the survivin inhibitor, YM155. Treatment with YM155 increased the release of cytochrome c, smac/DIABLO and apoptosis inducing-factor, and promoted loss of mitochondrial membrane potential, activation of Bax, recruitment of LC3-II to the autophagosomes and apoptosis in Bcl-xL silenced cells. We also found an additional mechanism for the augmentation of apoptosis due to abrogation of DNA double-strand break repair mediated by Rad51 repression and enhanced accumulation of γH2AX. In summary, our observations may provide a new insight into the link between Bcl-xL and survivin inhibition for the development of novel therapies for glioma. © 2016 Wiley Periodicals, Inc.

Anti-survivin effect of the small molecule inhibitor YM155 in RCC cells is mediated by time-dependent inhibition of the NF-κB pathway

“…YM155 has been a highly controversial anticancer agent since it was reported nearly a decade ago. Proclaimed as the first small molecule to suppress survivin, it soon became apparent that YM155 had pleiotropic effects, affecting diverse targets such as DNA 24 , and mitochondria as well as processes of which autophagy and the ER stress response have been implicated 11 . We have shown here that YM155 suppressed the NF-κB pathway through a sequence of events that culminated in the interception of the nuclear translocation of p65/p50.…”

“…While YM155 suppresses survivin levels in cancer cells, as confirmed in several investigations 7 – 10 , there is growing consensus that other oncogenic proteins or pathways are involved in its potent apoptogenic effects 11 – 13 . Earlier, we have shown that YM155 exhibited consistent nanomolar potencies across a panel of immortalized and patient derived RCC cell lines, independently of their VHL status and their survivin expression levels 13 .…”

Metabolite of ellagitannins, urolithin A induces autophagy and inhibits metastasis in human sw620 colorectal cancer cells

“…Colorectal cancer (CRC) is the second most common gastrointestinal cancer worldwide, and preventing tumor cell metastasis is important for prolonging patient survival . In recent years, the relationship between cancer and autophagy has been extensively studied, and autophagy can promote or inhibit tumor metastasis under different circumstance. Autophagy may exert an inhibitory effect in early stage tumors, reducing invasion, and metastasis.…”

Elucidating respective functions of two domains BIR and C-helix of human IAP survivin for precise targeted regulating mitotic cycle, apoptosis and autophagy of cancer cells

“…The loss of mitochondrial membrane potential was one of the typical characteristics of apoptosis [ 30 ]. In this study, the change of mitochondrial membrane potential in Bcap-37 cells treated with TAT-Survivin(T34/117A), TAT-BIR(T34A), and TAT-CC(T117A) for 48 h was detected using Rhodamine 123 and Hoechst33342 staining.…”