Abstract A100: STAT3 as a novel cancer prevention target in colorectal cancer stem cells

Abstract

Abstract Constitutive activation of signal transducers and activators of transcription 3 (STAT3) signaling is frequently detected in human cancer including colon cancer, and has emerged as an attractive molecular target for cancer prevention. Recent experimental evidence suggests that the existence of a small population of tumorigenic stem/progenitor cells may be responsible for tumor initiation, chemotherapy and radiation resistance, invasion, recurrence, and metastasis. An increasing body of evidence suggests that the cancer stem cell concept is also relevant to colorectal cancer. To date, however, whether STAT3 is activated in colon cancer stem cells or cancer-initiating cells and what the role of STAT3 signaling may play in these cancer stem cells is still unknown. If STAT3 is activated in colorectal cancer stem cells, inhibiting STAT3 may offer a promising opportunity to target colorectal cancer stem cells and prevent the recurrence of cancer. We utilized the colon cancer stem cells, which are characterized by an aldehyde dehydrogenase (ALDH)-positive (ALDH+) and CD133-positive (CD133+) subpopulation. We demonstrated that ALDH+/CD133+ cells have capacity than ALDH-/CD133- cells to form more tumorspheres and to exhibit more potent tumor-initiating ability in mice. We then examined the STAT3 activation in these colon cancer cells. Interestingly, we observed that the ALDH+/CD133+ subpopulation of colon cancer cells expressed higher levels of phosphorylated STAT3, an active form of STAT3, compared to the ALDH-/CD133- subpopulation and un-separated colon cancer cells, suggesting that STAT3 is activated in colon cancer stem cells. We demonstrated that dietary agent, curcumin and a new curcumin analog, GO-Y030 can inhibit STAT3 phosphorylation, cell viability, and induced apoptosis in colon cancer stem cells. The inhibition of STAT3 was confirmed using a novel STAT3-selecitve curcumin analog, FLLL32, STAT3 ShRNA, as well as STAT3 inhibitors, LLL12 and Stattic. All these STAT3 inhibitors, inhibited STAT3 phosphorylation, cell viability, and tumorsphere growth in colon cancer stem cells. Furthermore, both GO-Y030 and LLL12 inhibited tumor growth of colon cancer stem cells in NOD/SCID mouse model in vivo. In Summary, this is the first report to demonstrate that persistent STAT3 phosphorylation is expressed in colon cancer stem cells. Our study is also the first attempt to target STAT3 in colon cancer stem cells and we demonstrated for the first time that colon cancer stem cells are indeed sensitive to the inhibition by small molecular STAT3 inhibitors, FLLL32, LLL12, Stattic, STAT3 shRNA, and curcumin analog, GO-Y030. Our results suggest that STAT3 is a novel prevention target in colon cancer stem cells and inhibition of activated STAT3 in cancer stem cells may offer an effective preventive approach for colorectal carcinoma. Citation Information: Cancer Prev Res 2010;3(12 Suppl):A100.