Abstract
The activation of Notch signaling is implicated in tumorigenesis in the colon due to the induction of pro-survival signaling in colonic epithelial cells. Chemoresistance is a major obstacle for treatment and for the complete eradication of colorectal cancer (CRC); hence, the inhibition of Notch is an attractive target for CRC and several groups are working to identify small molecules or monoclonal antibodies that inhibit Notch or its downstream events; however, toxicity profiles in normal cells and organs often impede the clinical translation of these molecules. Dietary agents have gained momentum for targeting several pro-survival signaling cascades, and recent studies demonstrated that agents that inhibit Notch signaling result in growth inhibition in preclinical models of CRC. In this review, we focus on the importance of Notch as a preventive and therapeutic target for colon cancer and on the effect of WA on this signaling pathway in the context of colon cancer.
Similar content being viewed by others
References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Miyamoto S, Rosenberg DW. Role of Notch signaling in colon homeostasis and carcinogenesis. Cancer Sci. 2011;102(11):1938–42.
Jemal A et al. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.
Siegel R, Desantis C, Jemal A. Colorectal cancer statistics, 2014. CA Cancer J Clin. 2014;64(2):104–17.
Wu WK et al. Dysregulation and crosstalk of cellular signaling pathways in colon carcinogenesis. Crit Rev Oncol Hematol. 2013;86(3):251–77.
Noah TK, Shroyer NF. Notch in the intestine: regulation of homeostasis and pathogenesis. Annu Rev Physiol. 2013;75:263–88. This article describe the role of Notch in intestinal homeostasis and colorectal cancer.
Qiao L, Wong BC. Role of Notch signaling in colorectal cancer. Carcinogenesis. 2009;30(12):1979–86.
Barolo S, Posakony JW. Three habits of highly effective signaling pathways: principles of transcriptional control by developmental cell signaling. Genes Dev. 2002;16(10):1167–81.
van Tetering G et al. Metalloprotease ADAM10 is required for Notch1 site 2 cleavage. J Biol Chem. 2009;284(45):31018–27.
Meng RD et al. gamma-Secretase inhibitors abrogate oxaliplatin-induced activation of the Notch-1 signaling pathway in colon cancer cells resulting in enhanced chemosensitivity. Cancer Res. 2009;69(2):573–82.
Blaumueller CM et al. Intracellular cleavage of Notch leads to a heterodimeric receptor on the plasma membrane. Cell. 1997;90(2):281–91.
Fre S et al. Notch signals control the fate of immature progenitor cells in the intestine. Nature. 2005;435(7044):964–8.
Pellegrinet L et al. Dll1- and dll4-mediated notch signaling are required for homeostasis of intestinal stem cells. Gastroenterology. 2011;140(4):1230–40. e1-7.
Radtke F, Clevers H, Riccio O. From gut homeostasis to cancer. Curr Mol Med. 2006;6(3):275–89.
Zheng H et al. KLF4 gene expression is inhibited by the notch signaling pathway that controls goblet cell differentiation in mouse gastrointestinal tract. Am J Physiol Gastrointest Liver Physiol. 2009;296(3):G490–8.
Riccio O et al. Loss of intestinal crypt progenitor cells owing to inactivation of both Notch1 and Notch2 is accompanied by depression of CDK inhibitors p27Kip1 and p57Kip2. EMBO Rep. 2008;9(4):377–83.
Schroder N, Gossler A. Expression of Notch pathway components in fetal and adult mouse small intestine. Gene Expr Patterns. 2002;2(3–4):247–50.
Sander GR, Powell BC. Expression of notch receptors and ligands in the adult gut. J Histochem Cytochem. 2004;52(4):509–16.
VanDussen KL et al. Notch signaling modulates proliferation and differentiation of intestinal crypt base columnar stem cells. Development. 2012;139(3):488–97.
Vooijs M et al. Mapping the consequence of Notch1 proteolysis in vivo with NIP-CRE. Development. 2007;134(3):535–44.
Fre S et al. Notch lineages and activity in intestinal stem cells determined by a new set of knock-in mice. PLoS One. 2011;6(10):e25785.
Kosinski C et al. Gene expression patterns of human colon tops and basal crypts and BMP antagonists as intestinal stem cell niche factors. Proc Natl Acad Sci U S A. 2007;104(39):15418–23.
van Es JH et al. Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature. 2005;435(7044):959–63.
Stanger BZ et al. Direct regulation of intestinal fate by Notch. Proc Natl Acad Sci U S A. 2005;102(35):12443–8.
Fre S et al. Notch and Wnt signals cooperatively control cell proliferation and tumorigenesis in the intestine. Proc Natl Acad Sci U S A. 2009;106(15):6309–14.
Katoh M, Katoh M. Notch signaling in gastrointestinal tract (review). Int J Oncol. 2007;30(1):247–51.
Shroyer NF et al. Intestine-specific ablation of mouse atonal homolog 1 (Math1) reveals a role in cellular homeostasis. Gastroenterology. 2007;132(7):2478–88.
Yang Q et al. Requirement of Math1 for secretory cell lineage commitment in the mouse intestine. Science. 2001;294(5549):2155–8.
Zheng X et al. Suppression of hath1 gene expression directly regulated by hes1 via notch signaling is associated with goblet cell depletion in ulcerative colitis. Inflamm Bowel Dis. 2011;17(11):2251–60.
Schroeter EH, Kisslinger JA, Kopan R. Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain. Nature. 1998;393(6683):382–6.
Yin L, Velazquez OC, Liu ZJ. Notch signaling: emerging molecular targets for cancer therapy. Biochem Pharmacol. 2010;80(5):690–701.
Ellisen LW et al. TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell. 1991;66(4):649–61.
Pear WS et al. Exclusive development of T cell neoplasms in mice transplanted with bone marrow expressing activated Notch alleles. J Exp Med. 1996;183(5):2283–91.
Kimura K et al. Activation of Notch signaling in tumorigenesis of experimental pancreatic cancer induced by dimethylbenzanthracene in mice. Cancer Sci. 2007;98(2):155–62.
Wang Z et al. Down-regulation of notch-1 inhibits invasion by inactivation of nuclear factor-kappaB, vascular endothelial growth factor, and matrix metalloproteinase-9 in pancreatic cancer cells. Cancer Res. 2006;66(5):2778–84.
Mao J et al. ShRNA targeting Notch1 sensitizes breast cancer stem cell to paclitaxel. Int J Biochem Cell Biol. 2013;45(6):1064–73.
Reedijk M et al. High-level coexpression of JAG1 and NOTCH1 is observed in human breast cancer and is associated with poor overall survival. Cancer Res. 2005;65(18):8530–7.
Suman S, Das TP, Damodaran C. Silencing NOTCH signaling causes growth arrest in both breast cancer stem cells and breast cancer cells. Br J Cancer. 2013;109(10):2587–96.
Santagata S et al. JAGGED1 expression is associated with prostate cancer metastasis and recurrence. Cancer Res. 2004;64(19):6854–7.
Marignol L. Targeting notch in prostate cancer-combination is the key. Nat Rev Urol. 2014;11(7):419.
Kwon OJ et al. Increased Notch signalling inhibits anoikis and stimulates proliferation of prostate luminal epithelial cells. Nat Commun. 2014;5:4416.
Gao J et al. Expression of Jagged1 and its association with hepatitis B virus X protein in hepatocellular carcinoma. Biochem Biophys Res Commun. 2007;356(2):341–7.
Tripathi R et al. Clinical impact of de-regulated Notch-1 and Notch-3 in the development and progression of HPV-associated different histological subtypes of precancerous and cancerous lesions of human uterine cervix. PLoS One. 2014;9(6):e98642.
Ramdass B et al. Coexpression of Notch1 and NF-kappaB signaling pathway components in human cervical cancer progression. Gynecol Oncol. 2007;104(2):352–61.
Curry CL et al. Notch inhibition in Kaposi’s sarcoma tumor cells leads to mitotic catastrophe through nuclear factor-kappaB signaling. Mol Cancer Ther. 2007;6(7):1983–92.
Konishi J et al. Gamma-secretase inhibitor prevents Notch3 activation and reduces proliferation in human lung cancers. Cancer Res. 2007;67(17):8051–7.
Wang H et al. The expression of VEGF and Dll4/Notch pathway molecules in ovarian cancer. Clin Chim Acta. 2014;436C:243–8.
Jundt F et al. Activated Notch1 signaling promotes tumor cell proliferation and survival in Hodgkin and anaplastic large cell lymphoma. Blood. 2002;99(9):3398–403.
Sjolund J et al. Suppression of renal cell carcinoma growth by inhibition of Notch signaling in vitro and in vivo. J Clin Invest. 2008;118(1):217–28.
Ozawa T et al. Nuclear Notch3 expression is associated with tumor recurrence in patients with stage II and III colorectal cancer. Ann Surg Oncol. 2014;21(8):2650–8.
Dai Y et al. Silencing of Jagged1 inhibits cell growth and invasion in colorectal cancer. Cell Death Dis. 2014;5:e1170.
Farnie G et al. Novel cell culture technique for primary ductal carcinoma in situ: role of Notch and epidermal growth factor receptor signaling pathways. J Natl Cancer Inst. 2007;99(8):616–27.
Wong GT et al. Chronic treatment with the gamma-secretase inhibitor LY-411,575 inhibits beta-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J Biol Chem. 2004;279(13):12876–82.
Milano J et al. Modulation of notch processing by gamma-secretase inhibitors causes intestinal goblet cell metaplasia and induction of genes known to specify gut secretory lineage differentiation. Toxicol Sci. 2004;82(1):341–58.
Searfoss GH et al. Adipsin, a biomarker of gastrointestinal toxicity mediated by a functional gamma-secretase inhibitor. J Biol Chem. 2003;278(46):46107–16.
Veenendaal LM et al. Differential Notch and TGFbeta signaling in primary colorectal tumors and their corresponding metastases. Cell Oncol. 2008;30(1):1–11.
Rodilla V et al. Jagged1 is the pathological link between Wnt and Notch pathways in colorectal cancer. Proc Natl Acad Sci U S A. 2009;106(15):6315–20.
Espinoza I, Miele L. Notch inhibitors for cancer treatment. Pharmacol Ther. 2013;139(2):95–110. This review article describes the role of Notch signaling and apporoaches inhibit this signaling in various cancers.
Hayashi I et al. Neutralization of the gamma-secretase activity by monoclonal antibody against extracellular domain of nicastrin. Oncogene. 2012;31(6):787–98.
Funahashi Y et al. A notch1 ectodomain construct inhibits endothelial notch signaling, tumor growth, and angiogenesis. Cancer Res. 2008;68(12):4727–35.
Singh A et al. GSI promotes vincristine-induced apoptosis by enhancing multi-polar spindle formation. Cell Cycle. 2014;13(1):157–66.
Akiyoshi T et al. Gamma-secretase inhibitors enhance taxane-induced mitotic arrest and apoptosis in colon cancer cells. Gastroenterology. 2008;134(1):131–44.
Takebe N, Nguyen D, Yang SX. Targeting notch signaling pathway in cancer: clinical development advances and challenges. Pharmacol Ther. 2014;141(2):140–9. This recent review article describes the role of Notch signaling in cancer as well as the agents in use to target Notch signaling in different cancer types.
Timme CR, Gruidl M, Yeatman TJ. Gamma-secretase inhibition attenuates oxaliplatin-induced apoptosis through increased Mcl-1 and/or Bcl-xL in human colon cancer cells. Apoptosis. 2013;18(10):1163–74. It is a interesting study where authors have shown gamma-secretase inhibition resulted in decrease in oxaliplatin-induced apoptosis. This study warrants caution while treating colon cancer with the combination of GSIs and chemotherapy.
Herszenyi L et al. Chemoprevention of colorectal cancer: feasibility in everyday practice? Eur J Cancer Prev. 2008;17(6):502–14.
Cooper K et al. Chemoprevention of colorectal cancer: systematic review and economic evaluation. Health Technol Assess. 2010;14(32):1–206.
Gwyn K, Sinicrope FA. Chemoprevention of colorectal cancer. Am J Gastroenterol. 2002;97(1):13–21.
Surh YJ. Cancer chemoprevention with dietary phytochemicals. Nat Rev Cancer. 2003;3(10):768–80.
Vadodkar AS et al. Chemoprevention of breast cancer by dietary compounds. Anticancer Agents Med Chem. 2012;12(10):1185–202.
Mishra LC, Singh BB, Dagenais S. Scientific basis for the therapeutic use of Withania somnifera (Ashwagandha): a review. Altern Med Rev. 2000;5(4):334–46.
Malik F et al. A standardized root extract of Withania somnifera and its major constituent withanolide-A elicit humoral and cell-mediated immune responses by up regulation of Th1-dominant polarization in BALB/c mice. Life Sci. 2007;80(16):1525–38.
Malik F et al. Reactive oxygen species generation and mitochondrial dysfunction in the apoptotic cell death of human myeloid leukemia HL-60 cells by a dietary compound Withaferin A with concomitant protection by N-acetyl cysteine. Apoptosis. 2007;12(11):2115–33.
Malik F et al. Immune modulation and apoptosis induction: Two sides of antitumoural activity of a standardised herbal formulation of Withania somnifera. Eur J Cancer. 2009;45(8):1494–509.
Winters M. Ancient medicine, modern use: Withania somnifera and its potential role in integrative oncology. Altern Med Rev. 2006;11(4):269–77.
Vyas AR, Singh SV. Molecular targets and mechanisms of cancer prevention and treatment by withaferin a, a naturally occurring steroidal lactone. AAPS J. 2014;16(1):1–10. The authors have discussed the in vivo potential and molecular targets of WA contributing to its anticancer effects.
Mirjalili MH et al. Steroidal lactones from Withania somnifera, an ancient plant for novel medicine. Molecules. 2009;14(7):2373–93.
Bhattacharya SK, Satyan KS, Ghosal S. Antioxidant activity of glycowithanolides from Withania somnifera. Indian J Exp Biol. 1997;35(3):236–9.
Kaileh M et al. Withaferin a strongly elicits IkappaB kinase beta hyperphosphorylation concomitant with potent inhibition of its kinase activity. J Biol Chem. 2007;282(7):4253–64.
Jayaprakasam B et al. Growth inhibition of human tumor cell lines by withanolides from Withania somnifera leaves. Life Sci. 2003;74(1):125–32.
Mohan R et al. Withaferin A is a potent inhibitor of angiogenesis. Angiogenesis. 2004;7(2):115–22.
Bhattacharya SK et al. Effect of Withania somnifera glycowithanolides on a rat model of tardive dyskinesia. Phytomedicine. 2002;9(2):167–70.
Chowdhury K, Neogy RK. Mode of action of Withaferin A and Withanolide D. Biochem Pharmacol. 1975;24(8):919–20.
Sabina PE, Chandel S, Raool KM. Evaluation of analgesic, antipyretic and ulcerogenice effect of Withaferin A. Int J Integr Biol. 2009;6(2):52–6.
Lahat G et al. Vimentin is a novel anti-cancer therapeutic target; insights from in vitro and in vivo mice xenograft studies. PLoS One. 2010;5(4):e10105.
Koduru S et al. Notch-1 inhibition by Withaferin-A: a therapeutic target against colon carcinogenesis. Mol Cancer Ther. 2010;9(1):202–10.
Srinivasan S et al. Par-4-dependent apoptosis by the dietary compound Withaferin A in prostate cancer cells. Cancer Res. 2007;67(1):246–53.
Roy RV et al. Withaferin A, a steroidal lactone from Withania somnifera, induces mitotic catastrophe and growth arrest in prostate cancer cells. J Nat Prod. 2013;76(10):1909–15.
Lee J, Sehrawat A, Singh SV. Withaferin A causes activation of Notch2 and Notch4 in human breast cancer cells. Breast Cancer Res Treat. 2012;136(1):45–56. Authors have shown the effect of WA in breast cancer cells. They showed activation of Notch 2,4 and inactivation of Notch1 by WA. Notch 2 and Notch4 knockdown augmented WA mediated inhibition of cell migration.
Zhang X et al. Inhibition of cell growth and induction of apoptosis in ovarian carcinoma cell lines CaOV3 and SKOV3 by natural withanolide Withaferin A. Gynecol Oncol. 2012;124(3):606–12. Authors have shown WA mediated downregulation of Notch1 and 3 in ovarian cancer cells. This downregulation correlated with induction of apoptosis and cell cycle arrest.
Acknowledgments
This study was supported by NIH Grant 1R01CA185972-01.
Compliance with Ethics Guidelines
ᅟ
Conflict of Interest
Suman Suman, Trinath P. Das, Murali. K. Ankem, and Chendil Damodaran declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Suman, S., Das, T.P., Ankem, M.K. et al. Targeting Notch Signaling in Colorectal Cancer. Curr Colorectal Cancer Rep 10, 411–416 (2014). https://doi.org/10.1007/s11888-014-0252-3
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11888-014-0252-3