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      Targeting colon cancer stem cells using a new curcumin analogue, GO-Y030

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          Abstract

          Background:

          Persistent activation of signal transducers and activators of transcription 3 (STAT3) is commonly detected in many types of cancer, including colon cancer. To date, whether STAT3 is activated and the effects of STAT3 inhibition by a newly developed curcumin analogue, GO-Y030, in colon cancer stem cells are still unknown.

          Methods:

          Flow cytometry was used to isolate colon cancer stem cells, which are characterised by both aldehyde dehydrogenase (ALDH)-positive and CD133-positive subpopulations (ALDH +/CD133 +). The levels of STAT3 phosphorylation and the effects of STAT3 inhibition by a newly developed curcumin analogue, GO-Y030, that targets STAT3 in colon cancer stem cells were examined.

          Results:

          Our results observed that ALDH +/CD133 + colon cancer cells expressed higher levels of phosphorylated STAT3 than ALDH-negative/CD133-negative colon cancer cells, suggesting that STAT3 is activated in colon cancer stem cells. GO-Y030 and curcumin inhibited STAT3 phosphorylation, cell viability, tumoursphere formation in colon cancer stem cells. GO-Y030 also reduced STAT3 downstream target gene expression and induced apoptosis in colon cancer stem cells. Furthermore, GO-Y030 suppressed tumour growth of cancer stem cells from both SW480 and HCT-116 colon cancer cell lines in the mouse model.

          Conclusion:

          Our results indicate that STAT3 is a novel therapeutic target in colon cancer stem cells, and inhibition of activated STAT3 in cancer stem cells by GO-Y030 may offer an effective treatment for colorectal cancer.

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          Most cited references34

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          Stat3 as an oncogene.

          J F Bromberg, M H Wrzeszczynska, G Devgan … (1999)
          STATs are latent transcription factors that mediate cytokine- and growth factor-directed transcription. In many human cancers and transformed cell lines, Stat3 is persistently activated, and in cell culture, active Stat3 is either required for transformation, enhances transformation, or blocks apoptosis. We report that substitution of two cysteine residues within the C-terminal loop of the SH2 domain of Stat3 produces a molecule that dimerizes spontaneously, binds to DNA, and activates transcription. The Stat3-C molecule in immortalized fibroblasts causes cellular transformation scored by colony formation in soft agar and tumor formation in nude mice. Thus, the activated Stat3 molecule by itself can mediate cellular transformation and the experiments focus attention on the importance of constitutive Stat3 activation in human tumors.
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            A semiempirical free energy force field with charge-based desolvation.

            Ruth Huey, Garrett M. Morris, Arthur Olson … (2007)
            The authors describe the development and testing of a semiempirical free energy force field for use in AutoDock4 and similar grid-based docking methods. The force field is based on a comprehensive thermodynamic model that allows incorporation of intramolecular energies into the predicted free energy of binding. It also incorporates a charge-based method for evaluation of desolvation designed to use a typical set of atom types. The method has been calibrated on a set of 188 diverse protein-ligand complexes of known structure and binding energy, and tested on a set of 100 complexes of ligands with retroviral proteases. The force field shows improvement in redocking simulations over the previous AutoDock3 force field.
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              Aldehyde dehydrogenase 1 is a marker for normal and malignant human colonic stem cells (SC) and tracks SC overpopulation during colon tumorigenesis.

              Emina Huang, Mark J. Hynes, Tao Zhang … (2009)
              Although the concept that cancers originate from stem cells (SC) is becoming scientifically accepted, mechanisms by which SC contribute to tumor initiation and progression are largely unknown. For colorectal cancer (CRC), investigation of this problem has been hindered by a paucity of specific markers for identification and isolation of SC from normal and malignant colon. Accordingly, aldehyde dehydrogenase 1 (ALDH1) was investigated as a possible marker for identifying colonic SC and for tracking them during cancer progression. Immunostaining showed that ALDH1(+) cells are sparse and limited to the normal crypt bottom, where SCs reside. During progression from normal epithelium to mutant (APC) epithelium to adenoma, ALDH1(+) cells increased in number and became distributed farther up the crypt. CD133(+) and CD44(+) cells, which are more numerous and broadly distributed in normal crypts, showed similar changes during tumorigenesis. Flow cytometric isolation of cancer cells based on enzymatic activity of ALDH (Aldefluor assay) and implantation of these cells in nonobese diabetic-severe combined immunodeficient mice (a) generated xenograft tumors (Aldefluor(-) cells did not), (b) generated them after implanting as few as 25 cells, and (c) generated them dose dependently. Further isolation of cancer cells using a second marker (CD44(+) or CD133(+) serially) only modestly increased enrichment based on tumor-initiating ability. Thus, ALDH1 seems to be a specific marker for identifying, isolating, and tracking human colonic SC during CRC development. These findings also support our original hypothesis, derived previously from mathematical modeling of crypt dynamics, that progressive colonic SC overpopulation occurs during colon tumorigenesis and drives CRC development.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Br J Cancer
                Title: British Journal of Cancer
                Publisher: Nature Publishing Group
                ISSN (Print): 0007-0920
                ISSN (Electronic): 1532-1827
                Publication date (Print): 12 July 2011
                Publication date (Electronic): 21 June 2011
                Volume: 105
                Issue: 2
                Pages: 212-220
                Affiliations
                [1 ]simpleCenter 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
                [2 ]simpleDivision of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan 430030, China
                [3 ]simpleDivision of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University , Columbus, OH 43205, USA
                [4 ]simpleDepartmentof Clinical Oncology, Graduate school of medicine, Akita University , Akita, Japan
                [5 ]simpleDepartment of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University , Aobayama, Sendai 980-8578, Japan
                Author notes
                Article
                Publisher Item ID: bjc2011200
                DOI: 10.1038/bjc.2011.200
                PMC ID: 3142799
                PubMed ID: 21694723
                SO-VID: 5810f25f-dc06-499b-a87f-dba15de8316b
                Copyright © Copyright © 2011 Cancer Research UK
                History
                Date received : 20 December 2010
                Date revision received : 06 May 2011
                Date accepted : 11 May 2011
                Categories
                Subject: Translational Therapeutics

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: colon cancer,curcumin analogue,cancer stem cells,stat3,cd133,aldh
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: colon cancer, curcumin analogue, cancer stem cells, stat3, cd133, aldh

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