Extracellular, cell-permeable survivin inhibits apoptosis while promoting proliferative and metastatic potential
Open Access
- 17 March 2009
- journal article
- Published by Springer Science and Business Media LLC in British Journal of Cancer
- Vol. 100 (7), 1073-1086
- https://doi.org/10.1038/sj.bjc.6604978
Abstract
The tumour microenvironment is believed to be involved in development, growth, metastasis, and therapy resistance of many cancers. Here we show survivin, a member of the inhibitor of apoptosis protein (IAP) family, implicated in apoptosis inhibition and the regulation of mitosis in cancer cells, exists in a novel extracellular pool in tumour cells. Furthermore, we have constructed stable cell lines that provide the extracellular pool with either wild-type survivin (Surv-WT) or the previously described dominant-negative mutant survivin (Surv-T34A), which has proven pro-apoptotic effects in cancer cells but not in normal proliferating cells. Cancer cells grown in conditioned medium (CM) taken from Surv-WT cells absorbed survivin and experienced enhanced protection against genotoxic stresses. These cells also exhibited an increased replicative and metastatic potential, suggesting that survivin in the tumour microenvironment may be directly associated with malignant progression, further supporting survivin's function in tumourigenesis. Alternatively, cancer cells grown in CM taken from the Surv-T34A cells began to apoptose through a caspase-2- and caspase-9-dependent pathway that was further enhanced by the addition of other chemo- and radiotherapeutic modalities. Together our findings suggest a novel microenvironmental function for survivin in the control of cancer aggressiveness and spread, and should result in the genesis of additional cancer treatment modalities.Keywords
This publication has 47 references indexed in Scilit:
- Baicalein induces cancer cell death and proliferation retardation by the inhibition of CDC2 kinase and survivin associated with opposite role of p38 mitogen-activated protein kinase and AKTMolecular Cancer Therapeutics, 2007
- The Universal Character of the Tumor-Associated Antigen SurvivinClinical Cancer Research, 2007
- Extracellular survivin up-regulates adhesion molecules on the surface of leukocytes changing their reactivity patternJournal of Leukocyte Biology, 2007
- Drug Resistance and the Solid Tumor MicroenvironmentJNCI Journal of the National Cancer Institute, 2007
- Intracellular and Surface Distribution of Monocyte Tissue FactorArteriosclerosis, Thrombosis, and Vascular Biology, 2005
- Survivin, versatile modulation of cell division and apoptosis in cancerOncogene, 2003
- Survivin study: What is the next wave?Journal of Cellular Physiology, 2003
- Coordinated histone modifications mediated by a CtBP co-repressor complexNature, 2003
- The Hallmarks of CancerCell, 2000
- Stimulation of the transepithelial flux of influenza HA vaccine by cholera toxin B subunitVaccine, 1992