Curcumin Effects on the Wnt Signaling Pathway in Colorectal Cancer Stem Cells

  • Reyhaneh Moradi-Marjaneh Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh,Iran
  • Seyed Mahdi Hassanian Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran. Department of Medical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.Microanatomy Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
  • Soodabeh Shahidsales Cancer Research center, Mashhad University of Medical Sciences, Mashhad, Iran
  • Amir Avan Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran.Cancer Research center, Mashhad University of Medical Sciences, Mashhad, Iran.Department of Modern Sciences and Technologies, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
  • Majid Khazaei Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
Keywords: Wnt/β-catenin pathway, Colorectal cancer, Cancer stem cells


Colorectal cancer (CRC) is a leading cause of death worldwide. Despite improved treatment procedures, the disease rarely can be cured completely mainly because of recurrence. It is well evident that cancer recurrence is caused by cancer stem cells (CSCs), rare and immortal cells that can initiate and develop tumors and protect them against anticancer agents. CSCs are generated as a result of failures in intracellular signaling pathways of which Wnt/β-catenin has a key role in CRC. The Wnt/β-catenin signaling pathway is thought to be the major signaling in the maintenance of homeostasis of intestinal stem cells. Proliferation, upward migration of the colony crypt daughter cells, and differentiation into all epithelial cell types at least in part is regulated by Wnt/β-catenin signaling, suggesting its essential role during intestinal development and homeostasis. However, continuous activation of this signaling pathway in intestinal stem cells due to somatic mutations is a hallmark of most CRCs. Hence targeting Wnt/β-catenin signaling in CSCs can be a focus of new treatment strategies. Curcumin, the effective compound of plant Curcuma longa, has been studied as an anticancer agent. Recently, it has been shown that curcumin and its analogues decrease the risk of tumor recurrence by targeting CSCs via various cell signaling, in particular, Wnt/β-catenin pathway. In this review, we describe a relationship between Wnt-regulated CSCs and progression of CRC and the efficacy of curcumin and its analogues in targeting colorectal CSCs and also the Wnt/β-catenin molecular pathway involved.


Moradi-Marjaneh R, Hassanian SM, Fiuji H, Soleimanpour S, Ferns GA, Avan A, et al. Toll like receptor signaling path¬way as a potential therapeutic target in colorectal cancer. Journal of cellular physiology. 2017.

Clevers H. At the crossroads of inflammation and cancer. Cell. 2004;118(6):671-4.

Moradi Marjaneh R, Hassanian SM, Ghobadi N, Ferns GA, Karimi A, Jazayeri MH, et al. Targeting the death receptor signaling pathway as a potential therapeutic target in the treatment of colorectal cancer. J Cell Physiol. 2018.

Barker N, Ridgway RA, Van Es JH, Van De Weter¬ing M, Begthel H, Van Den Born M, et al. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature. 2009;457(7229):608-11.

Adams PD, Jasper H, Rudolph KL. Aging-induced stem cell mutations as drivers for disease and cancer. Cell stem cell. 2015;16(6):601-12.

Zeuner A, Todaro M, Stassi G, De Maria R. Colorectal can¬cer stem cells: from the crypt to the clinic. Cell stem cell. 2014;15(6):692-705.

Boland CR, Goel A. Microsatellite instability in colorectal cancer. Gastroenterology. 2010;138(6):2073-87. e3.

Wielenga VJ, Smits R, Korinek V, Smit L, Kielman M, Fod¬de R, et al. Expression of CD44 in Apc and TcfMutant Mice Implies Regulation by the WNT Pathway. The American journal of pathology. 1999;154(2):515-23.

Alison MR, Lim SM, Nicholson LJ. Cancer stem cells: prob¬lems for therapy? The Journal of pathology. 2011;223(2):148- 62.

Alvin A, Miller KI, Neilan BA. Exploring the potential of en¬dophytes from medicinal plants as sources of antimycobacte¬rial compounds. Microbiological research. 2014;169(7):483- 95.

Aggarwal BB, Sung B. Pharmacological basis for the role of curcumin in chronic diseases: an age-old spice with modern targets. Trends in pharmacological sciences. 2009;30(2):85- 94.

Shishodia S, Chaturvedi MM, Aggarwal BB. Role of cur¬cumin in cancer therapy. Current problems in cancer. 2007;31(4):243-305.

Hashemzehi M, Behnam-Rassouli R, Hassanian SM, Mora¬di-Binabaj M, Moradi-Marjaneh R, Rahmani F, et al. Phy¬tosomal-curcumin antagonizes cell growth and migration, induced by thrombin through AMP-Kinase in breast cancer. Journal of cellular biochemistry. 2018.

Anand P, Sundaram C, Jhurani S, Kunnumakkara AB, Ag¬garwal BB. Curcumin and cancer: an “old-age” disease with an “age-old” solution. Cancer letters. 2008;267(1):133-64.

Nishiya N, Oku Y, Kumagai Y, Sato Y, Yamaguchi E, Sasa¬ ki A, et al. A zebrafish chemical suppressor screening iden¬tifies small molecule inhibitors of the Wnt/β-catenin path¬way. Chemistry & biology. 2014;21(4):530-40.

Li Y, Zhang T. Targeting cancer stem cells by curcumin and clinical applications. Cancer letters. 2014;346(2):197-205.

Yan C, Jamaluddin MS, Aggarwal B, Myers J, Boyd DD. Gene expression profiling identifies activating transcription factor 3 as a novel contributor to the proapoptotic effect of curcumin. Molecular Cancer Therapeutics. 2005;4(2):233- 41.

Prasad CP, Rath G, Mathur S, Bhatnagar D, Ralhan R. Potent growth suppressive activity of curcumin in human breast cancer cells: Modulation of Wnt/β-catenin signaling. Chemico-biological interactions. 2009;181(2):263-71.

Chen F, Wang H, Xiang X, Yuan J, Chu W, Xue X, et al. Curcumin increased the differentiation rate of neurons in neural stem cells via wnt signaling in vitro study. Journal of Surgical Research. 2014;192(2):298-304.

Tiwari SK, Agarwal S, Seth B, Yadav A, Nair S, Bhatna¬gar P, et al. Curcumin-loaded nanoparticles potently in¬duce adult neurogenesis and reverse cognitive deficits in Alzheimer’s disease model via canonical Wnt/β-catenin pathway. ACS nano. 2013;8(1):76-103.

Kunwar A, Barik A, Mishra B, Rathinasamy K, Pandey R, Priyadarsini K. Quantitative cellular uptake, localization and cytotoxicity of curcumin in normal and tumor cells. Biochimica et Biophysica Acta (BBA)-General Subjects. 2008;1780(4):673-9.

Torchilin V. Multifunctional and stimuli-sensitive pharma¬ceutical nanocarriers. European Journal of Pharmaceutics and Biopharmaceutics. 2009;71(3):431-44.

Devadasu VR, Bhardwaj V, Kumar MR. Can controversial nanotechnology promise drug delivery? Chemical reviews. 2012;113(3):1686-735.

Maeda H, Wu J, Sawa T, Matsumura Y, Hori K. Tumor vascular permeability and the EPR effect in macromolecu¬lar therapeutics: a review. Journal of controlled release. 2000;65(1):271-84.

Torchilin V. Tumor delivery of macromolecular drugs based on the EPR effect. Advanced drug delivery reviews. 2011;63(3):131-5.

Guo D, Li Q, Lv Q, Wei Q, Cao S, Gu J. MiR-27a targets sFRP1 in hFOB cells to regulate proliferation, apoptosis and differentiation. PLoS One. 2014;9(3):e91354.

Willert K, Brown JD, Danenberg E, Duncan AW, Weissman IL, Reya T, et al. Wnt proteins are lipid-modified and can act as stem cell growth factors. Nature. 2003;423(6938):448-52.

Yang VW. APC as a checkpoint gene: the beginning or the end? Gastroenterology. 2002;123(3):935-9.

Cong F, Schweizer L, Varmus H. Wnt signals across the plasma membrane to activate the β-catenin pathway by forming oligomers containing its receptors, Frizzled and LRP. Development. 2004;131(20):5103-15.

He X, Semenov M, Tamai K, Zeng X. LDL receptor-related proteins 5 and 6 in Wnt/β-catenin signaling: arrows point the way. Development. 2004;131(8):1663-77.

Korinek V, Barker N, Morin PJ, van Wichen D, de Weger R, Kinzler KW, et al. Constitutive transcriptional activation by a β-catenin-Tcf complex in APC−/− colon carcinoma. Science. 1997;275(5307):1784-7.

Aberle H, Bauer A, Stappert J, Kispert A, Kemler R. β-cat¬enin is a target for the ubiquitin–proteasome pathway. The EMBO journal. 1997;16(13):3797-804.

Kitagawa M, Hatakeyama S, Shirane M, Matsumoto M, Ishida N, Hattori K, et al. An F-box protein, FWD1, me¬diates ubiquitin-dependent proteolysis of β-catenin. The EMBO journal. 1999;18(9):2401-10.

Winston JT, Strack P, Beer-Romero P, Chu CY, Elledge SJ, Harper JW. The SCFβ-TRCP–ubiquitin ligase complex as¬sociates specifically with phosphorylated destruction motifs in IκBα and β-catenin and stimulates IκBα ubiquitination in vitro. Genes & development. 1999;13(3):270-83.

Hart MJ, de los Santos R, Albert IN, Rubinfeld B, Polakis P. Downregulation of β-catenin by human Axin and its as¬sociation with the APC tumor suppressor, β-catenin and GSK3β. Current Biology. 1998;8(10):573-81.

Rubinfeld B, Albert I, Porfiri E, Fiol C. Binding of GSK¬3beta to teh APC-beta-catenin complex and regulation of complex assembly. Science. 1996;272(5264):1023.

Kishida S, Yamamoto H, Ikeda S, Kishida M, Sakamoto I, Koyama S, et al. Axin, a negative regulator of the wnt signa¬ling pathway, directly interacts with adenomatous polyposis coli and regulates the stabilization of β-catenin. Journal of Biological Chemistry. 1998;273(18):10823-6.

Davidson G, Wu W, Shen J, Bilic J, Fenger U, Stannek P, et al. Casein kinase 1 γ couples Wnt receptor activation to cy¬toplasmic signal transduction. Nature. 2005;438(7069):867- 72.

Zeng X, Tamai K, Doble B, Li S, Huang H, Habas R, et al. A dual-kinase mechanism for Wnt co-receptor phosphoryla¬tion and activation. Nature. 2005;438(7069):873-7.

Lee E, Salic A, Krüger R, Heinrich R, Kirschner MW. The roles of APC and Axin derived from experimental and theoretical analysis of the Wnt pathway. PLoS Biol. 2003;1(1):e10.

Cong F, Varmus H. Nuclear-cytoplasmic shuttling of Axin regulates subcellular localization of β-catenin. Proceedings of the National Academy of Sciences of the United States of America. 2004;101(9):2882-7.

Brennan K, Gonzalez-Sancho JM, Castelo-Soccio LA, Howe LR, Brown AM. Truncated mutants of the putative Wnt re¬ceptor LRP6/Arrow can stabilize β-catenin independently of Frizzled proteins. Oncogene. 2004;23(28):4873-84.

Gao C, Chen Y-G. Dishevelled: The hub of Wnt signaling. Cellular signalling. 2010;22(5):717-27.

Sharma M, Castro-Piedras I, Simmons GE, Pruitt K. Dishev¬elled: A masterful conductor of complex Wnt signals. Cellu¬lar signalling. 2018.

van Noort M, Clevers H. TCF transcription factors, media¬tors of Wnt-signaling in development and cancer. Develop¬mental biology. 2002;244(1):1-8.

Cavallo RA, Cox RT, Moline MM, Roose J, Polevoy GA, Clevers H, et al. Drosophila Tcf and Groucho in¬teract to repress Wingless signalling activity. Nature. 1998;395(6702):604-8.

Adachi S, Jigami T, Yasui T, Nakano T, Ohwada S, Omori Y, et al. Role of a BCL9-related β-catenin-binding protein, B9L, in tumorigenesis induced by aberrant activation of Wnt signaling. Cancer research. 2004;64(23):8496-501.

He T-C, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT, et al. Identification of c-MYC as a target of the APC pathway. Science. 1998;281(5382):1509-12.

Sansom OJ, Reed KR, van de Wetering M, Muncan V, Win¬ton DJ, Clevers H, et al. Cyclin D1 is not an immediate tar¬get of β-catenin following Apc loss in the intestine. Journal of Biological Chemistry. 2005;280(31):28463-7.

Brabletz T, Jung A, Dag S, Hlubek F, Kirchner T. β-Catenin regulates the expression of the matrix metalloproteinase-7 in human colorectal cancer. The American journal of patholo¬gy. 1999;155(4):1033-8.

Takahashi M, Tsunoda T, Seiki M, Nakamura Y, Furukawa Y. Identification of membrane-type matrix metalloprotein¬ase-1 as a target of the beta-catenin/Tcf4 complex in human colorectal cancers. Oncogene. 2002;21(38):5861-7.

Hlubek F, Spaderna S, Jung A, Kirchner T, Brabletz T. β-Catenin activates a coordinated expression of the proin¬vasive factors laminin-5 γ2 chain and MT1-MMP in colorectal carcinomas. International Journal of Cancer. 2004;108(2):321-6.

Batlle E, Henderson JT, Beghtel H, van den Born MM, San¬cho E, Huls G, et al. β-Catenin and TCF mediate cell posi¬tioning in the intestinal epithelium by controlling the expres¬sion of EphB/ephrinB. Cell. 2002;111(2):251-63.

Batlle E, Bacani J, Begthel H, Jonkeer S, Gregorieff A, van de Born M, et al. EphB receptor activity suppresses colorec¬tal cancer progression. Nature. 2005;435(7045):1126-30.

Herbst A, Bommer GT, Kriegl L, Jung A, Behrens A, Csan¬adi E, et al. ITF-2 is disrupted via allelic loss of chromosome 18q21, and ITF-2B expression is lost at the adenoma-carci¬noma transition. Gastroenterology. 2009;137(2):639-48. e9.

Hovanes K, Li TW, Munguia JE, Truong T, Milovanovic T, Marsh JL, et al. β-catenin–sensitive isoforms of lymphoid enhancer factor-1 are selectively expressed in colon cancer. Nature genetics. 2001;28(1):53-7.

Roose J, Huls G, Van Beest M, Moerer P, Van Der Horn K, Goldschmeding R, et al. Synergy between tumor sup¬pressor APC and the β-catenin-Tcf4 target Tcf1. Science. 1999;285(5435):1923-6.

Jho E-h, Zhang T, Domon C, Joo C-K, Freund J-N, Costan¬tini F. Wnt/β-catenin/Tcf signaling induces the transcription of Axin2, a negative regulator of the signaling pathway. Mo¬lecular and cellular biology. 2002;22(4):1172-83.

Leung JY, Kolligs FT, Wu R, Zhai Y, Kuick R, Hanash S, et al. Activation of AXIN2 Expression by β-Catenin-T Cell Factor A FEEDBACK REPRESSOR PATHWAY REGU¬LATING Wnt SIGNALING. Journal of Biological Chemis¬try. 2002;277(24):21657-65.

Lustig B, Jerchow B, Sachs M, Weiler S, Pietsch T, Karsten U, et al. Negative feedback loop of Wnt signaling through upregulation of conductin/axin2 in colorectal and liver tum¬ors. Molecular and cellular biology. 2002;22(4):1184-93.

Rousset R, Mack JA, Wharton KA, Axelrod JD, Cadigan KM, Fish MP, et al. Naked cuticle targets dishevelled to antagonize Wnt signal transduction. Genes & development. 2001;15(6):658-71.

Hao H-X, Xie Y, Zhang Y, Charlat O, Oster E, Avello M, et al. ZNRF3 promotes Wnt receptor turnover in an R-spon¬din-sensitive manner. Nature. 2012;485(7397):195-200.

Koo B-K, Spit M, Jordens I, Low TY, Stange DE, van de Wetering M, et al. Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors. Nature. 2012;488(7413):665-9.

Jiang X, Charlat O, Zamponi R, Yang Y, Cong F. Dishev¬elled promotes Wnt receptor degradation through recruit¬ment of ZNRF3/RNF43 E3 ubiquitin ligases. Molecular cell. 2015;58(3):522-33.

De Lau WB, Snel B, Clevers HC. The R-spondin protein family. Genome biology. 2012;13(3):1.

Jin Y-R, Yoon JK. The R-spondin family of proteins: emerg¬ing regulators of WNT signaling. The international journal of biochemistry & cell biology. 2012;44(12):2278-87.

Peng WC, de Lau W, Forneris F, Granneman JC, Huch M, Clevers H, et al. Structure of stem cell growth factor R-spon¬din 1 in complex with the ectodomain of its receptor LGR5 Cell reports. 2013;3(6):1885-92.

Peng WC, de Lau W, Madoori PK, Forneris F, Granneman JC, Clevers H, et al. Structures of Wnt-antagonist ZNRF3 and its complex with R-spondin 1 and implications for sign¬aling. PLoS One. 2013;8(12):e83110.

Wang D, Huang B, Zhang S, Yu X, Wu W, Wang X. Struc¬tural basis for R-spondin recognition by LGR4/5/6 recep¬tors. Genes & development. 2013;27(12):1339-44.

Hao H-X, Jiang X, Cong F. Control of Wnt Receptor Turno¬ver by R-spondin-ZNRF3/RNF43 Signaling Module and Its Dysregulation in Cancer. Cancers. 2016;8(6):54.

Van der Flier LG, Clevers H. Stem cells, self-renewal, and differentiation in the intestinal epithelium. Annual review of physiology. 2009;71:241-60.

Umar S. Intestinal stem cells. Current gastroenterology re¬ports. 2010;12(5):340-8.

Van der Flier LG, Sabates–Bellver J, Oving I, Haegebarth A, De Palo M, Anti M, et al. The intestinal Wnt/TCF signa¬ture. Gastroenterology. 2007;132(2):628-32.

Barker N, Van Es JH, Kuipers J, Kujala P, Van Den Born M, Cozijnsen M, et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature. 2007;449(7165):1003-7.

Schepers AG, Vries R, Van Den Born M, Van De Wetering M, Clevers H. Lgr5 intestinal stem cells have high telomer¬ase activity and randomly segregate their chromosomes. The EMBO journal. 2011;30(6):1104-9.

van der Flier LG, van Gijn ME, Hatzis P, Kujala P, Hae¬gebarth A, Stange DE, et al. Transcription factor achaete scute-like 2 controls intestinal stem cell fate. Cell. 2009;136(5):903-12.

Muñoz J, Stange DE, Schepers AG, van de Wetering M, Koo BK, Itzkovitz S, et al. The Lgr5 intestinal stem cell signature: robust expression of proposed quiescent ‘+ 4’cell markers. The EMBO journal. 2012;31(14):3079-91.

Koo B-K, van Es JH, van den Born M, Clevers H. Porcupine inhibitor suppresses paracrine Wnt-driven growth of Rnf43; Znrf3-mutant neoplasia. Proceedings of the National Acad¬emy of Sciences. 2015;112(24):7548-50.

Van Limbergen J, Geddes K, Henderson P, Russell RK, Drummond HE, Satsangi J, et al. Paneth cell marker CD24 in NOD2 knockout organoids and in inflammatory bowel disease (IBD). Gut. 2013:gutjnl-2013-305077.

Zeilstra J, Joosten S, Van Andel H, Tolg C, Berns A, Snoek M, et al. Stem cell CD44v isoforms promote intestinal can¬cer formation in Apc (min) mice downstream of Wnt signa¬ling. Oncogene. 2014;33(5):665-70.

Snippert HJ, van Es JH, van den Born M, Begthel H, Stange DE, Barker N, et al. Prominin-1/CD133 marks stem cells and early progenitors in mouse small intestine. Gastroenter¬ology. 2009;136(7):2187-94. e1.

Levin TG, Powell AE, Davies PS, Silk AD, Dismuke AD, Anderson EC, et al. Characterization of the intestinal cancer stem cell marker CD166 in the human and mouse gastro¬intestinal tract. Gastroenterology. 2010;139(6):2072-82. e5.

Maria Cambuli F, Rezza A, Nadjar J, Plateroti M. Brief report: Musashi1-eGFP mice, a new tool for differential isolation of the intestinal stem cell populations. Stem cells. 2013;31(10):2273-8.

Potten CS. Stem cells in gastrointestinal epithelium: num¬bers, characteristics and death. Philosophical Transactions of the Royal Society of London B: Biological Sciences. 1998;353(1370):821-30.

Sangiorgi E, Capecchi MR. Bmi1 is expressed in vivo in intestinal stem cells. Nature genetics. 2008;40(7):915-20.

Tian H, Biehs B, Warming S, Leong KG, Rangell L, Klein OD, et al. A reserve stem cell population in small intestine renders Lgr5-positive cells dispensable. Nature. 2011;478(7368):255.

Montgomery RK, Carlone DL, Richmond CA, Farilla L, Kranendonk ME, Henderson DE, et al. Mouse telomer¬ase reverse transcriptase (mTert) expression marks slowly cycling intestinal stem cells. Proceedings of the National Academy of Sciences. 2011;108(1):179-84.

Powell AE, Wang Y, Li Y, Poulin EJ, Means AL, Wash¬ington MK, et al. The pan-ErbB negative regulator Lrig1 is an intestinal stem cell marker that functions as a tumor suppressor. Cell. 2012;149(1):146-58.

Takeda N, Jain R, LeBoeuf MR, Wang Q, Lu MM, Epstein JA. Interconversion between intestinal stem cell populations in distinct niches. Science. 2011;334(6061):1420-4.

Potten CS, Owen G, Booth D. Intestinal stem cells protect their genome by selective segregation of template DNA strands. J Cell Sci. 2002;115(11):2381-8.

Cui S, Chang P-Y. Current understanding concerning in¬testinal stem cells. World Journal of Gastroenterology. 2016;22(31):7099.

Gregorieff A, Pinto D, Begthel H, Destrée O, Kielman M, Clevers H. Expression pattern of Wnt signaling components in the adult intestine. Gastroenterology. 2005;129(2):626- 38.

Sato T, Clevers H. Growing self-organizing mini-guts from a single intestinal stem cell: mechanism and applications. Science. 2013;340(6137):1190-4.

Bahrami A, Khazaei M, Hassanian SM, ShahidSales S, Joudi-Mashhad M, Maftouh M, et al. Targeting the tumor microenvironment as a potential therapeutic approach in colorectal cancer: Rational and progress. J Cell Physiol. 2018;233(4):2928-36.

Roth S, Fodde R. The nature of intestinal stem cells’ nur¬ture. EMBO reports. 2011;12(6):483-4.

Binnerts ME, Kim K-A, Bright JM, Patel SM, Tran K, Zhou M, et al. R-Spondin1 regulates Wnt signaling by inhibiting internalization of LRP6. Proceedings of the National Acad¬emy of Sciences. 2007;104(37):14700-5.

Noren NK, Pasquale EB. Eph receptor–ephrin bidirectional signals that target Ras and Rho proteins. Cellular signal¬ling. 2004;16(6):655-66.

Ohlstein B, Spradling A. Multipotent Drosophila intestinal stem cells specify daughter cell fates by differential notch signaling. Science. 2007;315(5814):988-92.

Sato T, Van Es JH, Snippert HJ, Stange DE, Vries RG, Van Den Born M, et al. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature. 2011;469(7330):415.

Dick JE. Stem cell concepts renew cancer research. Blood. 2008;112(13):4793-807.

Todaro M, Alea MP, Di Stefano AB, Cammareri P, Ver¬meulen L, Iovino F, et al. Colon cancer stem cells dictate tumor growth and resist cell death by production of inter¬leukin-4. Cell stem cell. 2007;1(4):389-402.

Ramasamy TS, Ayob AZ, Myint HHL, Thiagarajah S, Amini F. Targeting colorectal cancer stem cells using cur¬cumin and curcumin analogues: insights into the mecha¬nism of the therapeutic efficacy. Cancer cell international. 2015;15(1):96.

Dou H, Shen R, Tao J, Huang L, Shi H, Chen H, et al. Curcumin suppresses the colon cancer proliferation by in¬hibiting Wnt/β-catenin pathways via miR-130a. Frontiers in pharmacology. 2017;8:877.

Tarapore RS, Siddiqui IA, Mukhtar H. Modulation of Wn¬t/β-catenin signaling pathway by bioactive food compo¬nents. Carcinogenesis. 2011;33(3):483-91.

Marjaneh RM, Rahmani F, Hassanian SM, Rezaei N, Hashemzehi M, Bahrami A, et al. Phytosomal curcumin in¬hibits tumor growth in colitis-associated colorectal cancer. Journal of Cellular Physiology.

Schmitt M, Metzger M, Gradl D, Davidson G, Orian-Rous¬seau V. CD44 functions in Wnt signaling by regulating LRP6 localization and activation. Cell Death & Differen¬tiation. 2015;22(4):677-89.

Rappa G, Mercapide J, Anzanello F, Le TT, Johlfs MG, Fiscus RR, et al. Wnt interaction and extracellular release of prominin-1/CD133 in human malignant melanoma cells. Experimental cell research. 2013;319(6):810-9.

Cojoc M, Peitzsch C, Kurth I, Trautmann F, Kunz- Schughart LA, Telegeev GD, et al. Aldehyde dehydro¬genase is regulated by β-catenin/TCF and promotes ra¬dioresistance in prostate cancer progenitor cells. Cancer research. 2015;75(7):1482-94.

Chai R, Xia A, Wang T, Jan TA, Hayashi T, Berming¬ham-McDonogh O, et al. Dynamic expression of Lgr5, a Wnt target gene, in the developing and mature mouse coch¬lea. Journal of the Association for Research in Otolaryngol¬ogy. 2011;12(4):455-69.

Rao G-h, Liu H-m, Li B-w, Hao J-j, Yang Y-l, Wang M-r, et al. Establishment of a human colorectal cancer cell line P6C with stem cell properties and resistance to chemothera¬peutic drugs. Acta Pharmacologica Sinica. 2013;34(6):793.

Kakarala M, Brenner DE, Korkaya H, Cheng C, Tazi K, Ginestier C, et al. Targeting breast stem cells with the can¬cer preventive compounds curcumin and piperine. Breast cancer research and treatment. 2010;122(3):777-85.

Nautiyal J, Kanwar SS, Yu Y, Majumdar AP. Combination of dasatinib and curcumin eliminates chemo-resistant colon cancer cells. Journal of molecular signaling. 2011;6(1):7.

Yu Y, Kanwar SS, Patel BB, Nautiyal J, Sarkar FH, Ma¬jumdar AP. Elimination of colon cancer stem-like cells by the combination of curcumin and FOLFOX. Translational oncology. 2009;2(4):321-8.

Fong D, Yeh A, Naftalovich R, Choi TH, Chan MM. Cur¬cumin inhibits the side population (SP) phenotype of the rat C6 glioma cell line: towards targeting of cancer stem cells with phytochemicals. Cancer letters. 2010;293(1):65-72.

Howells LM, Sale S, Sriramareddy SN, Irving GR, Jones DJ, Ottley CJ, et al. Curcumin ameliorates oxaliplatin-in¬duced chemoresistance in HCT116 colorectal cancer cells in vitro and in vivo. International Journal of Cancer. 2011;129(2):476-86.

Zhang S, Yu D. Targeting Src family kinases in anti-cancer therapies: turning promise into triumph. Trends in pharma¬cological sciences. 2012;33(3):122-8.

Kantara C, O’Connell M, Sarkar S, Moya S, Ullrich R, Sin¬gh P. Curcumin promotes autophagic survival of a subset of colon cancer stem cells, which are ablated by DCLK1-siR¬NA. Cancer research. 2014;74(9):2487-98.

Kim E, Davidson LA, Zoh RS, Hensel ME, Salinas ML, Patil BS, et al. Rapidly cycling Lgr5+ stem cells are exqui¬sitely sensitive to extrinsic dietary factors that modulate co¬lon cancer risk. Cell Death & Disease. 2016;7(11):e2460.

Tajbakhsh A, Hasanzadeh M, Rezaee M, Khedri M, Khaz¬aei M, ShahidSales S, et al. Therapeutic potential of novel formulated forms of curcumin in the treatment of breast cancer by the targeting of cellular and and physiological dys¬regulated pathways. J Cell Physiol. 2018;233(3):2183-92

Wang K, Zhang T, Liu L, Wang X, Wu P, Chen Z, et al. Novel micelle formulation of curcumin for enhancing an¬titumor activity and inhibiting colorectal cancer stem cells. Int J Nanomedicine. 2012;7:4487-97.

Kanwar SS, Yu Y, Nautiyal J, Patel BB, Padhye S, Sarkar FH, et al. Difluorinated-curcumin (CDF): a novel curcumin analog is a potent inhibitor of colon cancer stem-like cells. Pharmaceutical research. 2011;28(4):827-38.

Sharma RA, McLelland HR, Hill KA, Ireson CR, Euden SA, Manson MM, et al. Pharmacodynamic and pharmacokinet¬ic study of oral Curcuma extract in patients with colorectal cancer. Clinical Cancer Research. 2001;7(7):1894-900.

Cheng A-L, Hsu C-H, Lin J-K, Hsu M-M, Ho Y-F, Shen T-S, et al. Phase I clinical trial of curcumin, a chemopre¬ventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res. 2001;21(4B):2895-900.

Sharma RA, Euden SA, Platton SL, Cooke DN, Shafayat A, Hewitt HR, et al. Phase I clinical trial of oral curcumin. Clinical Cancer Research. 2004;10(20):6847-54.

Garcea G, Berry DP, Jones DJ, Singh R, Dennison AR, Farmer PB, et al. Consumption of the putative chemopre¬ventive agent curcumin by cancer patients: assessment of curcumin levels in the colorectum and their pharmacody¬namic consequences. Cancer Epidemiology and Prevention Biomarkers. 2005;14(1):120-5.

He Z-Y, Shi C-B, Wen H, Li F-L, Wang B-L, Wang J. Upregulation of p53 expression in patients with colorectal cancer by administration of curcumin. Cancer investiga¬tion. 2011;29(3):208-13.

Carroll RE, Benya RV, Turgeon DK, Vareed S, Neuman M, Rodriguez L, et al. Phase IIa clinical trial of curcumin for the prevention of colorectal neoplasia. Cancer preven¬tion research. 2011;4(3):354-64.

Irving GR, Howells LM, Sale S, Kralj-Hans I, Atkin WS, Clark SK, et al. Prolonged biologically active colonic tissue levels of curcumin achieved after oral administration—a clinical pilot study including assessment of patient accepta¬bility. Cancer prevention research. 2013;6(2):119-28.

Itzkowitz SH, Yio X. Inflammation and cancer IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation. American Journal of Physiology-Gastro¬intestinal and Liver Physiology. 2004;287(1):G7-G17.

Jurenka JS. Anti-inflammatory properties of curcumin, a major constituent of Curcuma longa: a review of preclin¬ical and clinical research. Alternative medicine review. 2009;14(2).

Holt PR, Katz S, Kirshoff R. Curcumin therapy in inflam¬matory bowel disease: a pilot study. Digestive diseases and sciences. 2005;50(11):2191-3.

Hanai H, Iida T, Takeuchi K, Watanabe F, Maruyama Y, Andoh A, et al. Curcumin maintenance therapy for ulcer¬ative colitis: randomized, multicenter, double-blind, place¬bo-controlled trial. Clinical Gastroenterology and Hepatol¬ogy. 2006;4(12):1502-6.

Singla V, Mouli VP, Garg SK, Rai T, Choudhury BN, Ver¬ma P, et al. Induction with NCB-02 (curcumin) enema for mild-to-moderate distal ulcerative colitis—a randomized, placebo-controlled, pilot study. Journal of Crohn’s and Co¬litis. 2014;8(3):208-14.

How to Cite
Moradi-Marjaneh R, Hassanian SM, Shahidsales S, Avan A, Khazaei M. Curcumin Effects on the Wnt Signaling Pathway in Colorectal Cancer Stem Cells. Basic Clin Cancer Res. 10(2):33-8.