Targeting Cancer Stem Cells in Castration-Resistant Prostate Cancer

Abstract

Purpose Clinical evidence suggests an increased CSC in tumor mass may contribute to the failure of conventional therapies since CSCs seem to be more resistant than differentiated tumor cells. Thus, unveiling the mechanism regulating CSCs and candidate target molecules will provide new strategy to cure the patients. Experimental design The stem-like cell properties were determined by a prostasphere assay, and dye exclusion assay. To find critical stem cell marker and reveal regulation mechanism, basic biochemical and molecular biological methods such as qRT-PCR, Western blot, reporter gene assay and chromatin immunoprecipitation assay were employed. In addition, to determine the effect of combination therapy targeting both CSCs and its progeny, in vitro MTT assay and in vivo xenograft model was used. Results We demonstrate immortalized normal human prostate epithelial cells, appeared non-tumorigenic in vivo, become tumorigenic and acquire stem cell phenotype after knocking down a tumor suppressor gene. Also, those stem-like cells increase chemoresistance to conventional anti-cancer reagent. Mechanistically, we unveil that Wnt signaling is a key pathway regulating well-known stem cell marker CD44 by directly interacting to the promoter. Thus, by targeting CSCs using Wnt inhibitors synergistically enhances the efficacy of conventional drugs. Furthermore, the in vivo mice model bearing xenografts showed a robust inhibition of tumor growth after combination therapy. Conclusions Overall, this study provides strong evidence of CSC in CRPC. This new combination therapy strategy targeting CSC could significantly enhance therapeutic efficacy of current chemotherapy regimen only targeting non-CSC cells.

Sensitization of Radioresistant Prostate Cancer Cells by Resveratrol Isolated from Arachis hypogaea Stems

“…Treatment of DAB2IP-deficient PCa cells with high-dose radiation even at 10 Gy, showed no significant apoptosis [10]. In addition, downregulation of DAB2IP increased the EMT and enriched the cancer stem cell population of the PCa cells [50]. This established line of evidence indicates that DAB2IP knockdown-induced radioresistant PCa cells could be successfully used to evaluate the mechanism underlying the potential radiosensitization induced by PSE and RV.…”

Inhibiting the SUMO Pathway Represses the Cancer Stem Cell Population in Breast and Colorectal Carcinomas

“…Anti-CD44 antibodies have been utilized as one means of specifically targeting the CSC population (Arabi et al., 2015, Liu and Jiang, 2006, Molejon et al., 2015). Other approaches to target the CSC population via CD44 have been based on altering transcriptional pathways regulating CD44 expression including Wnt (Yun et al., 2016), FOXP3 (Zhang et al., 2015), SMURF1 (Khammanivong et al., 2014), and Bmi-1 (Yu et al., 2014). Our current findings indicate that SUMO inhibitors can repress expression of CD44 in the CSC population through a TFAP2A-dependent mechanism.…”

Isolation and functional interrogation of adult human prostate epithelial stem cells at single cell resolution

“…Advances in prostate cancer research have identified resident cancer stem-like cells that are intrinsically resistant to standard treatments and reseed tumor growth following ablative therapies (Chen et al, 2016; Collins et al, 2005; Yun et al, 2016). Furthermore, gene profiling analysis has shown that prostate cancer increases in a stem-like state as it progresses from organ-confined to metastatic disease (Smith et al, 2015).…”