Abstract
Abstract Increasing evidence has indicated the role of cancer stem cell (CSC) in the progression toward to more aggressive cancer. CSC is defined as a tumor initiating population that are capable of self-renewal and also regenerate fast-proliferative tumor cell progeny. Especially, CSCs appear to be more resistant than highly proliferative tumor cells to conventional therapies, which could explain therapeutic failure. Thus, CSCs have been recognized as important candidate targets to cure the patient. In prostate cancer (PCa), castration resistance prostate cancer (CRPC) is an end-stage, incurable disease and associated with the majority of mortality. CRPCa is characterized to be androgen-independent and express many specific genes from basal cells that contain stem cell population. Also, some evidence suggests CRPC possessing CSC phenotypes. In this study, we employed several non-tumorigenic, immortalized normal human prostate epithelial cells derived from basal cell population as a model to study the relationship of CSC with CRPC. These cells express unique stem cell markers (CD44high/CD24low) from profiling stem cell gene expression, acquire stem cell phenotypes based on prostatesphere and side population assays after knocking down a novel tumor suppressor gene-DAB2IP that is involved in cell trans-differentiation such as epithelial-to-mesenchymal transition (EMT). These cells become highly tumorigenic with very low cell number using in vitro colony formation and anchorage-independent assays and in vivo xenograft model. Also, these cells are highly resistant to chemotherapeutic agent or radiotherapy. From a tissue microarray study, we observed a significant correlation of CD44 expression determined by immunohistochemical staining with advanced stage of PCa specimens. CD44 is not only a stem cell marker but also plays a key role in CSC formation. Mechanistically, CD44 expression is regulated by Wnt signaling in which DAB2IP functions as a potent scaffold protein to recruit PP2A and GSK3β inhibit β-catenin activation. Thus, by targeting this pathway using Wnt-specific small molecular inhibitors can reduce CSC population and synergistically enhances the drug effect of conventional chemotherapy. Furthermore, using in vivo CSC model, combination therapy exhibited a synergistic effect on tumor growth. Taken together, this study provides a strong evidence of the relationship of CSC with CRPC. It also offers a new and promising therapeutic strategy targeting CSC as well as proliferative non-CSC cell population in hope to eradicate tumor initiating cell and its progeny population simultaneously. Citation Format: Eun-Jin Yun, Elizabeth Hernandez, Jer-Tsong Hsieh. Targeting cancer stem cell to enhance therapeutic efficacy of prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4234. doi:10.1158/1538-7445.AM2015-4234
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