Abstract
STAT3 is constitutively activated in colon cancer but its contributions in cancer-initiating cells have not been explored. In this study, we characterized STAT3 in aldehyde dehydrogenase (ALDH)-positive (ALDH(+)) and CD133-positive (CD133(+)) subpopulations of human colon tumor cells that exhibited more potent tumor-initiating ability than ALDH(-)/CD133(-) cells in tumor xenograft assays in mice. We found that ALDH(+)/CD133(+) cells expressed higher levels of the active phosphorylated form of STAT3 than either ALDH(-)/CD133(-) or unfractionated colon cancer cells. STAT3 inhibition by RNA interference-mediated knockdown or small-molecule inhibitors LLL12 or Stattic blocked downstream target gene expression, cell viability, and tumorsphere-forming capacity in cancer-initiating cells. Similarly, treatment of mouse tumor xenografts with STAT3 short hairpin RNA (shRNA), interleukin 6 shRNA, or LLL12 inhibited tumor growth. Our results establish that STAT3 is constitutively activated in colon cancer-initiating cells and that these cells are sensitive to STAT3 inhibition. These findings establish a powerful rationale to develop STAT3 inhibitory strategies for treating advanced colorectal cancers.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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AC133 Antigen
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Aldehyde Dehydrogenase / metabolism
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Aldehyde Dehydrogenase 1 Family
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Animals
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Anthraquinones / pharmacology
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Antigens, CD / metabolism
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Cell Growth Processes / physiology
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Cell Line, Tumor
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Cell Survival / drug effects
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Cell Survival / genetics
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Colonic Neoplasms / genetics
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Colonic Neoplasms / metabolism
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Colonic Neoplasms / pathology*
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Cyclic S-Oxides / pharmacology
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Female
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Gene Expression / drug effects
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Gene Knockdown Techniques / methods
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Glycoproteins / metabolism
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HCT116 Cells
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HT29 Cells
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Humans
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Interleukin-6 / genetics
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Isoenzymes / genetics
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Mice
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Mice, Inbred NOD
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Mice, SCID
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Neoplastic Stem Cells / drug effects
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Neoplastic Stem Cells / metabolism
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Neoplastic Stem Cells / pathology*
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Peptides / metabolism
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Phosphorylation / drug effects
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RNA Interference
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RNA, Small Interfering / administration & dosage
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RNA, Small Interfering / genetics
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Retinal Dehydrogenase / genetics
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STAT3 Transcription Factor / antagonists & inhibitors
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STAT3 Transcription Factor / genetics
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STAT3 Transcription Factor / metabolism*
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Sulfonamides / pharmacology
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Xenograft Model Antitumor Assays / methods
Substances
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AC133 Antigen
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Anthraquinones
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Antigens, CD
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Cyclic S-Oxides
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Glycoproteins
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IL6 protein, human
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Interleukin-6
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Isoenzymes
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LLL12 compound
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PROM1 protein, human
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Peptides
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Prom1 protein, mouse
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RNA, Small Interfering
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STAT3 Transcription Factor
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STAT3 protein, human
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Sulfonamides
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stattic
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Aldehyde Dehydrogenase 1 Family
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Aldehyde Dehydrogenase
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ALDH1A1 protein, human
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ALDH1A1 protein, mouse
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Retinal Dehydrogenase