title: STAT3 signaling pathway is necessary for cell survival and tumorsphere forming capacity in ALDH⁺/CD133⁺ stem cell-like human colon cancer cells.
abstract: Persistent activation of Signal Transducers and Activators of Transcription 3 (STAT3) is frequently detected in colon cancer. Increasing evidence suggests the existence of a small population of colon cancer stem or cancer-initiating cells may be responsible for tumor initiation, metastasis, and resistance to chemotherapy and radiation. Whether STAT3 plays a role in colon cancer-initiating cells and the effect of STAT3 inhibition is still unknown. Flow cytometry was used to isolate colon cancer stem-like cells from three independent human colon cancer cell lines characterized by both aldehyde dehydrogenase (ALDH)-positive and CD133-positive subpopulation (ALDH(+)/CD133(+)). The effects of STAT3 inhibition in colon cancer stem-like cells were examined. The phosphorylated or activated form of STAT3 was expressed in colon cancer stem-like cells and was reduced by a STAT3-selective small molecular inhibitor, FLLL32. FLLL32 also inhibited the expression of potential STAT3 downstream target genes in colon cancer stem-like cells including survivin, Bcl-XL, as well as Notch-1, -3, and -4, which may be involved in stem cell function. Furthermore, FLLL32 inhibited cell viability and tumorsphere formation as well as induced cleaved caspase-3 in colon cancer stem-like cells. FLLL32 is more potent than curcumin as evidenced with lower IC50 in colon cancer stem-like cells. In summary, our results indicate that STAT3 is a novel therapeutic target in colon cancer stem-like cells and inhibition of STAT3 in cancer stem-like cells may offer a potential treatment for colorectal cancer.
authors.affiliation: Center for Childhood Cancer, The Research Institute at Nationwide Children's Hospital, Department of Pediatrics, Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH 43205, USA. lin.796@osu.edu
authors.forename: Li
authors.initials: L
authors.lastname: Lin
authors.forename: James
authors.initials: J
authors.lastname: Fuchs
authors.forename: Chenglong
authors.initials: C
authors.lastname: Li
authors.forename: Veronica
authors.initials: V
authors.lastname: Olson
authors.forename: Tanios
authors.initials: T
authors.lastname: Bekaii-Saab
authors.forename: Jiayuh
authors.initials: J
authors.lastname: Lin
mesh_terms: D000071916:AC133 Antigen; D000080924:Aldehyde Dehydrogenase 1 Family; D015703:Antigens, CD / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D003474:Curcumin / Q000031:analogs & derivatives / Q000494:pharmacology; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D010455:Peptides / Q000378:metabolism; D010766:Phosphorylation; D050697:Retinal Dehydrogenase / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; C548902:FLLL 32; D006023:Glycoproteins; D007527:Isoenzymes; C000606023:PROM1 protein, human; D010455:Peptides; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000080924:Aldehyde Dehydrogenase 1 Family; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase; D003474:Curcumin