Mitochondrial survivin inhibits apoptosis and promotes tumorigenesis

Abstract

Evasion of apoptosis is a hallmark of cancer, but the molecular circuitries of this process are not understood. Here we show that survivin, a member of the inhibitor of apoptosis gene family that is overexpressed in cancer, exists in a novel mitochondrial pool in tumor cells. In response to cell death stimulation, mitochondrial survivin is rapidly discharged in the cytosol, where it prevents caspase activation and inhibits apoptosis. Selective targeting of survivin to mitochondria enhances colony formation in soft agar, accelerates tumor growth in immunocompromised animals, and abolishes tumor cell apoptosis in vivo. Therefore, mitochondrial survivin orchestrates a novel pathway of apoptosis inhibition, which contributes to tumor progression.

Regulation of survivin expression by IGF-1/mTOR signaling

“…Protein-normalized (50 mg) extracts were separated on 12% SDS polyacrylamide gels, transferred to PVDF membranes (Millipore, Billerica, MA, USA) and analysed by immunoblotting, as described (Dohi et al, 2004). Antibodies to b-actin (1:5000, clone AC-15, Sigma), survivin (1:1000, NOVUS Biologicals, Littleton, CO, USA), XIAP (1:500, BD Bioscience, San Jose, CA, USA) or total p70S6K (1:500, Cell Signaling, Danvers, MA, USA) were used with detection by chemiluminescence (Plus Reagents, GE Healthcare, Piscataway, NJ, USA).…”

“…These include rapid changes in survivin protein stability modulated by phosphorylation (O' Connor et al, 2000), subcellular trafficking controlled by monoubiquitination (Vong et al, 2005) and dynamic exchange of survivin pools among individual subcellular compartments (Dohi et al, 2004). In prostate cancer, a plethora of molecular pathways has been associated with modulation of survivin levels, including extracellular matrix-integrin interactions (Fornaro et al, 2003), antiandrogen therapy (Zhang et al, 2005), Stat3 activation (Nam et al, 2005) and Smad/BMP-7 signaling (Yang et al, 2006), thus contributing to apoptosis resistance.…”

Tumor-Released Survivin Induces a Type-2 T Cell Response and Decreases Cytotoxic T Cell Function, in Vitro

“…One tumor antigen recently shown to be released from cancer cells into the extracellular space is the inhibitor of apoptosis (IAP) protein Survivin [34,35]. Within the cancer cell, Survivin functions to prevent cell death in response to apoptotic signals [36,37]. In its extracellular context, Survivin is released and taken up by surrounding malignant cells, which increases their proliferative rate, resistance to therapy and their invasive potential [34].…”

The effects of knockdown of wild-type survivin, survivin-2B or survivin-Δ3 on the radiosensitization in a soft tissue sarcoma cells in vitro under different oxygen conditions

“…34,35 Thus, one mechanism for survivin-2B-related induction of apoptosis is to block mitochondrial-localized survivin delivery into the cytosol by their physical interaction. 10,29 Therefore, the knockdown of survivin-2B may release wild-type survivin and inhibit apoptosis after a stimulus like irradiation.…”

“…3,4 Survivin is a multifunctional protein that suppresses apoptosis and regulates cell cycle progression. [5][6][7][8][9][10] Furthermore, human survivin is negatively regulated by wild-type p53. [11][12][13][14] In a previous study, in five soft tissue sarcoma cell lines a reduced plating efficiency and occurrence of polyploidy independent of the p53 gene status was observed after treatment with survivin-specific siRNA.…”