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Curcumin promotes autophagic survival of a subset of colon cancer stem cells, which are ablated by DCLK1-siRNA.

Significance Statement

Cancer remains one of the leading causes of death in the United States. Currently available therapies, such as chemo/radiotherapy, target the bulk of the tumor cells. But cancer stem cells (CSCs) are resistant to many of these treatments, and grow back into metastatic tumors, causing relapse of the disease. There is thus a critical need for developing new therapies which specifically target cancer stem cells. Cancer and normal stem cells share expression of many marker proteins. It is thus important to specifically target cancer stem cells while sparing normal stem cells, to avoid toxic effects to the body. Dietary agents are generally non-toxic to normal cells and many have been found to reduce growth of cancer cells.  One such dietary agent is curcumin, which has been extensively studied and exerts anti-tumorigenic effects, when administered in pharmacological concentrations or delivered as bioavailable formulations.  The effect on specific colon cancer stem cell populations, however, had remained unexamined. We therefore examined inhibitory potency against colon cancer stem cell populations which co-expressed DCLK1/Lgr5 with CD44 (hallmark of transformed/cancer stem cells).  Our studies led us to an unexpected finding that a sub-set of DCLK1+ve cells were resistant to curcumin; after a period of dormancy, the DCLK1+ve cells re-grew as spheroids in a novel relapse assay developed by us. We therefore examined the effect of down regulating DCLK1 expression (using DCLK- siRNA) in colon cancer cells/tumors. Surprisingly, loss of DCLK1 was more potent than curcumin in inhibiting growth of colon cancer cells as spheroids/xenografts in vivo. Combination of DCLK1-siRNA +curcumin was most effective in eliminating cancer stem cells populations positive for the indicated markers and in shrinking the tumors below pre-treatment sizes. In summary, curcumin alone eliminated cancer stem cells positive for LGR5 and/or CD44, and promoted autophagic survival of cancer stem cells positive for DCLK1. Thus a sub-set of DCLK1+ cancer stem cells evaded pro-apoptotic effects of curcumin, and underwent autophagic survival by as yet unknown mechanisms.  Combination of curcumin+DCLK1-siRNA eliminated cancer stem cells positive for the three stem-cell-markers, with an absence of tumor relapse. We have therefore demonstrated for the first time that targeting DCLK1+ve CSCs along with curcumin and/or other therapies maybe required for eliminating cancer stem cells and avoiding relapse of the disease. Developing such novel therapeutics will spare normal stem cells from drug-induced damage and target the root cause of cancer spread (CSCs), thus preventing relapse of the disease.

Curcumin Promotes Autophagic Survival of a Sub-Set of Colon Cancer Stem Cells, which are Ablated by DCLK1-siRNA

 

 

 

 

 

 

 

 

Kantara C, O’Connell M, Sarkar S, Moya S, Ullrich R, Singh P.

Cancer Res. 2014 May 1;74(9):2487-98.

Departments of Neuroscience and Cell Biology and Sealy Cancer Center, University of Texas Medical Branch Health, Galveston, Texas.

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 cancer stem cells, 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 cancer stem cells. 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 cancer stem cells and highlight DCLK1 as a target to enhance antitumor properties of curcumin.

©2014 AACR.

 

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