期刊
INTERNATIONAL JOURNAL OF ONCOLOGY
卷 44, 期 5, 页码 1470-1480出版社
SPANDIDOS PUBL LTD
DOI: 10.3892/ijo.2014.2335
关键词
cancer stem cells; prostate cancer; apoptosis resistance
类别
资金
- German Cancer Aid (Deutsche Krebshilfe) [109362]
- German Research Community (DFG) [HE 3186/11-1]
- Federal Ministry of Education and Research (BMBF) [031A213]
- German-Israeli Foundation for Scientific Research and Development (GIF) [1058-7.11/2008]
- Heidelberger Stiftung Chirurgie
- Stiftung fur Krebs und Scharlachforschung
- Hanns A. Pielenz Stiftung
Advanced androgen-independent prostate cancer (AIPC) is an aggressive malignancy with a poor prognosis. Apoptosis-resistant cancer stem cells (CSCs) have been identified in AIPC and are not eliminated by current therapeutics. Novel therapeutic options, which are currently being evaluated in patient studies, include TRAIL and the broccoli-derived isothiocyanate sulforaphane. Although neither agent targets normal cells, TRAIL induces apoptosis in most cancer cells, and sulforaphane eliminates CSCs. In this study, the established AIPC cell lines DU145 and PC3, with enriched CSC features, and primary patient-derived prostate CSCs were treated with sulforaphane and recombinant soluble TRAIL. We examined the effects of these drugs on NF-kappa B activity, self-renewal and differentiation potential, and stem cell signaling via spheroid- and colony-forming assays, FACS and western blot analyses, immunohistochemistry, and an antibody protein array in vitro and after xenotransplantation. We largely found a stronger effect of sulforaphane on CSC properties compared to TRAIL, though the agents acted synergistically when applied in combination. This was associated with the inhibition of TRAIL-induced NF-kappa B binding; CXCR4, Jagged1, Notch 1, SOX 2, and Nanog expression; ALDH1 activity inhibition; and the elimination of differentiation and self-renewal potential. In vivo, tumor engraftment and tumor growth were strongly inhibited, without the induction of liver necrosis or other obvious side effects. These findings suggest that sulforaphane shifts the balance from TRAIL-induced survival signals to apoptosis and thus explains the observed synergistic effect. A nutritional strategy for high sulforaphane intake may target the cancer-specific activity of TRAIL in CSCs.
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