PDF file - 2102KB, Colon cancer cells positive for DCLK1, co-express CD44, while Lgr5+ve cells do not (S1). Localization of cells expressing DCLK1/Lgr5/CD44 within spheroidal growths (S2). Effect of curcumin on relative expression of indicated proteins in HCT-116 cells, growing as either 2D monolayers, or 3D spheroids or xenografts in athymic nude mice (S3). Curcumin induces autophagy in HCT-116 cells in culture (S4). Effect of curcumin�DCLK1-siRNA on levels of LC3-I/II and PCNA staining and on stem cell populations in HCT-116 xenografts (S5).
ARTICLE ABSTRACT
Curcumin is known to induce apoptosis of cancer cells by different mechanisms, but its effects on cancer stem cells (CSC) have been less investigated. Here, we report that curcumin promotes the survival of DCLK1-positive colon CSCs, potentially confounding application of its anticancer properties. At optimal concentrations, curcumin greatly reduced expression levels of stem cell markers (DCLK1/CD44/ALDHA1/Lgr5/Nanog) in three-dimensional spheroid cultures and tumor xenografts derived from colon cancer cells. However, curcumin unexpectedly induced proliferation and autophagic survival of a subset of DCLK1-positive CSCs. Spheroid cultures were disintegrated by curcumin in vitro but regrew within 30 to 40 days of treatment, suggesting a survival benefit from autophagy, permitting long-term persistence of colorectal cancer. Notably, RNA interference–mediated silencing of DCLK1 triggered apoptotic cell death of colon cancer cells in vitro and in vivo, and abolished colorectal cancer survival in response to curcumin; combination of DCLK1-siRNA and curcumin dramatically reversed CSC phenotype, contributing to attenuation of the growth of spheroid cultures and tumor xenografts. Taken together, our findings confirm a role of DCLK1 in colon CSCs and highlight DCLK1 as a target to enhance antitumor properties of curcumin. Cancer Res; 74(9); 2487–98. ©2014 AACR.
