title: Curcumin promotes autophagic survival of a subset of colon cancer stem cells, which are ablated by DCLK1-siRNA.
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.
authors.affiliation: Authors' Affiliations: Departments of Neuroscience and Cell Biology and Sealy Cancer Center, University of Texas Medical Branch Health, Galveston, Texas.
authors.forename: Carla
authors.initials: C
authors.lastname: Kantara
authors.forename: Malaney
authors.initials: M
authors.lastname: O'Connell
authors.forename: Shubhashish
authors.initials: S
authors.lastname: Sarkar
authors.forename: Stephanie
authors.initials: S
authors.lastname: Moya
authors.forename: Robert
authors.initials: R
authors.lastname: Ullrich
authors.forename: Pomila
authors.initials: P
authors.lastname: Singh
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000473:pathology; D003474:Curcumin / Q000494:pharmacology*; D000089742:Doublecortin-Like Kinases; D005260:Female; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D018874:Spheroids, Cellular / Q000201:enzymology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D047908:Intracellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; C117347:DCLK1 protein, human; D000089742:Doublecortin-Like Kinases; D017346:Protein Serine-Threonine Kinases; D003474:Curcumin