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 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 RNAi-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 shRNA, IL-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.

PMID: 21900397 [PubMed - as supplied by publisher] Source: National Library of Medicine.