Nuclear Receptors as Potential Pharmacological Targets for Colorectal Cancer Therapy via Regulating Wnt/β-catenin Signaling
Main Article Content
Abstract
Hyperactivation of the Wnt/β-catenin signaling pathway due to mutations in its components initiates the majority of colorectal cancer (CRC) cases and promotes CRC development. Unphosphorylated β-catenin accumulates in the nuclear and interacts with TCF/LEF factors to stimulate the transcription of the downstream target genes of Wnt/β-catenin signaling. Therefore, the suppression of dysregulated Wnt/β-catenin signaling is considered as a promising strategy for CRC therapy. In the past decade, accumulating evidence revealed that nuclear receptors (NRs) modulated Wnt/β-catenin signaling activity via binding to diverse members of this pathway. In this review, we mainly focus on the regulation and the underlying mechanisms of Wnt/β-catenin signaling by NRs and their ligands or pharmacological modulators. Their potential in the precise treatment and individualized therapy for colorectal cancer is also discussed.
Article Details
How to Cite
HU, Tianhui et al.
Nuclear Receptors as Potential Pharmacological Targets for Colorectal Cancer Therapy via Regulating Wnt/β-catenin Signaling.
Medical Research Archives, [S.l.], v. 4, n. 7, nov. 2016.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/812>. Date accessed: 20 apr. 2024.
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
[1] Hollman DA, Milona A, van Erpecum KJ, et al. Anti-inflammatory and metabolic actions of FXR: insights into molecular mechanisms. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids. 2012; 1821(11):1443-52.
[2] Barbier O, Torra IP, Duguay Y, et al. Pleiotropic actions of peroxisome proliferator–activated receptors in lipid metabolism and atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology. 2002; 22(5):717-26.
[3] Pascual-García M, Valledor AF. Biological roles of liver X receptors in immune cells. Archivum immunologiae et therapiae experimentalis. 2012; 60(4):235-49.
[4] Wu Y, Yu D-d, Yan D-l, et al. Liver X receptor as a drug target for the treatment of breast cancer. Anti-cancer drugs. 2016; 27(5):373-82.
[5] Xiao X, Wang P, Chou K-C. Recent progresses in identifying nuclear receptors and their families. Current topics in medicinal chemistry. 2013; 13(10):1192-200.
[6] Helsen C, Claessens F. Looking at nuclear receptors from a new angle. Molecular and cellular endocrinology. 2014; 382(1):97-106.
[7] Dawson MI, Xia Z. The retinoid X receptors and their ligands. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids. 2012; 1821(1):21-56.
[8] Korzh V. Winding roots of Wnts. Zebrafish. 2008; 5(3):159-68.
[9] Sugimura R, Li L. Noncanonical Wnt signaling in vertebrate development, stem cells, and diseases. Birth Defects Research Part C: Embryo Today: Reviews. 2010; 90(4):243-56.
[10] Reya T, Clevers H. Wnt signalling in stem cells and cancer. Nature. 2005; 434(7035):843-50.
[11] Logan CY, Nusse R. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol. 2004; 20:781-810.
[12] Powell SM, Zilz N, Beazer-Barclay Y, et al. APC mutations occur early during colorectal tumorigenesis. Nature. 1992; 359(6392):235-7.
[13] Behrens J, von Kries JP, Kühl M, et al. Functional interaction of β-catenin with the transcription factor LEF-1. Nature. 1996; 382(6592):638-42.
[14] Molenaar M, Van De Wetering M, Oosterwegel M, et al. XTcf-3 transcription factor mediates β-catenin-induced axis formation in Xenopus embryos. Cell. 1996; 86(3):391-9.
[15] He T-C, Sparks AB, Rago C, et al. Identification of c-MYC as a target of the APC pathway. Science. 1998; 281(5382):1509-12.
[16] Tetsu O, McCormick F. β-Catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature. 1999; 398(6726):422-6.
[17] He L, Lu N, Dai Q, et al. Wogonin induced G1 cell cycle arrest by regulating Wnt/β-catenin signaling pathway and inactivating CDK8 in human colorectal cancer carcinoma cells. Toxicology. 2013; 312:36-47.
[18] Yang M, Li S-N, Anjum KM, et al. A double-negative feedback loop between Wnt–β-catenin signaling and HNF4α regulates epithelial–mesenchymal transition in hepatocellular carcinoma. J Cell Sci. 2013; 126(24):5692-703.
[19] Mulholland DJ, Dedhar S, Coetzee GA, et al. Interaction of nuclear receptors with the Wnt/β-catenin/Tcf signaling axis: Wnt you like to know? Endocrine reviews. 2005; 26(7):898-915.
[20] Xiao J-H, Ghosn C, Hinchman C, et al. Adenomatous polyposis coli (APC)-independent regulation of β-catenin degradation via a retinoid X receptor-mediated pathway. Journal of Biological Chemistry. 2003; 278(32):29954-62.
[21] Pálmer HG, González-Sancho JM, Espada J, et al. Vitamin D3 promotes the differentiation of colon carcinoma cells by the induction of E-cadherin and the inhibition of β-catenin signaling. The Journal of cell biology. 2001; 154(2):369-88.
[22] Cao X, Liu W, Lin F, et al. Retinoid X receptor regulates Nur77/TR3-dependent apoptosis [corrected] by modulating its nuclear export and mitochondrial targeting. Molecular and cellular biology. 2004; 24(22):9705-25.
[23] Zhang X-k. Targeting Nur77 translocation. Expert opinion on therapeutic targets. 2007; 11(1):69-79.
[24] Lin X-F, Zhao B-X, Chen H-Z, et al. RXRα acts as a carrier for TR3 nuclear export in a 9-cis retinoic acid-dependent manner in gastric cancer cells. Journal of cell science. 2004; 117(23):5609-21.
[25] Ahuja H, Szanto A, Nagy L, et al. The retinoid X receptor and its ligands: versatile regulators of metabolic function, cell differentiation and cell death. Journal of biological regulators and homeostatic agents. 2003; 17(1):29-45.
[26] Liu B, Lee K-W, Li H, et al. Combination therapy of insulin-like growth factor binding protein-3 and retinoid X receptor ligands synergize on prostate cancer cell apoptosis in vitro and in vivo. Clinical cancer research. 2005; 11(13):4851-6.
[27] de Lera ÁR, Krezel W, Rühl R. An Endogenous Mammalian Retinoid X Receptor Ligand, At Last! ChemMedChem. 2016; 11(10):1027-37.
[28] Han A, Tong C, Hu D, et al. A direct protein-protein interaction is involved in the suppression of β-catenin transcription by retinoid X receptor α in colorectal cancer cells. Cancer biology & therapy. 2008; 7(3):454-9.
[29] Dillard AC, Lane MA. Retinol increases β-catenin-RXRα binding leading to the increased proteasomal degradation of β-catenin and RXRα. Nutrition and cancer. 2007; 60(1):97-108.
[30] Zhang F, Meng F, Li H, et al. Suppression of retinoid X receptor alpha and aberrant β-catenin expression significantly associates with progression of colorectal carcinoma. European Journal of Cancer. 2011; 47(13):2060-7.
[31] Haussler MR, Haussler CA, Bartik L, et al. Vitamin D receptor: molecular signaling and actions of nutritional ligands in disease prevention. Nutrition reviews. 2008; 66(suppl 2):S98-S112.
[32] Bikle DD. Vitamin D receptor, a tumor suppressor in skin 1. Canadian journal of physiology and pharmacology. 2014; 93(5):349-54.
[33] Maestro MA, Molnár F, Mouriño A, et al. Vitamin D receptor 2016: novel ligands and structural insights. Expert Opinion on Therapeutic Patents. 2016:1-16.
[34] Ge Z, Hao M, Xu M, et al. Novel nonsecosteroidal VDR ligands with phenyl-pyrrolyl pentane skeleton for cancer therapy. European journal of medicinal chemistry. 2016; 107:48-62.
[35] Egan JB, Thompson PA, Vitanov MV, et al. Vitamin D receptor ligands, adenomatous polyposis coli, and the vitamin D receptor FokI polymorphism collectively modulate β‐catenin activity in colon cancer cells. Molecular carcinogenesis. 2010; 49(4):337-52.
[36] Larriba MJ, Ordóñez-Morán P, Chicote I, et al. Vitamin D receptor deficiency enhances Wnt/β-catenin signaling and tumor burden in colon cancer. PloS one. 2011; 6(8):e23524.
[37] Pálmer HG, Larriba MJ, García JM, et al. The transcription factor SNAIL represses vitamin D receptor expression and responsiveness in human colon cancer. Nature medicine. 2004; 10(9):917-9.
[38] Larriba MJ, Martín-Villar E, García JM, et al. Snail2 cooperates with Snail1 in the repression of vitamin D receptor in colon cancer. Carcinogenesis. 2009; 30(8):1459-68.
[39] Larriba MJ, Valle N, Pálmer HG, et al. The inhibition of Wnt/β-catenin signalling by 1α, 25-dihydroxyvitamin D3 is abrogated by Snail1 in human colon cancer cells. Endocrine-Related Cancer. 2007; 14(1):141-51.
[40] Pendas-Franco N, Aguilera O, Pereira F, et al. Vitamin D and Wnt/β-catenin pathway in colon cancer: role and regulation of DICKKOPF genes. Anticancer Research. 2008; 28(5A):2613-23.
[41] Ahearn TU, Shaukat A, Flanders WD, et al. A randomized clinical trial of the effects of supplemental calcium and vitamin D3 on the APC/β-catenin pathway in the normal mucosa of colorectal adenoma patients. Cancer Prevention Research. 2012; 5(10):1247-56.
[42] Huerta S, Irwin RW, Heber D, et al. 1alpha, 25-(OH)(2)-D (3) and its synthetic analogue decrease tumor load in theApc (min) Mouse. Cancer Research. 1(62):741-6.
[43] Xu H, Posner GH, Stevenson M, et al. ApcMIN modulation of vitamin D secosteroid growth control. Carcinogenesis. 2010; 31(8):1434-41.
[44] Polvani S, Tarocchi M, Tempesti S, et al. Peroxisome proliferator activated receptors at the crossroad of obesity, diabetes, and pancreatic cancer. World journal of gastroenterology. 2016; 22(8):2441.
[45] Reddy AT, Lakshmi SP, Reddy RC. PPARγ as a Novel Therapeutic Target in Lung Cancer. PPAR Research. 2016; 2016.
[46] Sikka S, Chen L, Sethi G, et al. Targeting PPARγ signaling cascade for the prevention and treatment of prostate cancer. PPAR research. 2012; 2012.
[47] Zhang J, Liu X, Xie XB, et al. Multitargeted bioactive ligands for PPARs discovered in the last decade. Chemical Biology & Drug Design. 2016.
[48] Liu J, Wang H, Zuo Y, et al. Functional interaction between peroxisome proliferator-activated receptor γ and β-catenin. Molecular and cellular biology. 2006; 26(15):5827-37.
[49] Moldes M, Ying Z, Morrison RF, et al. Peroxisome-proliferator-activated receptor γ suppresses Wnt/β-catenin signalling during adipogenesis. Biochemical Journal. 2003; 376(3):607-13.
[50] Lu D, Carson DA. Repression of β-catenin signaling by PPARγ ligands. European journal of pharmacology. 2010; 636(1):198-202.
[51] Guo F, Ren X, Dong Y, et al. Constitutive expression of PPARγ inhibits proliferation and migration of gastric cancer cells and down-regulates Wnt/β-Catenin signaling pathway downstream target genes TERT and ENAH. Gene. 2016; 584(1):31-7.
[52] Fujisawa T, Nakajima A, Fujisawa N, et al. Peroxisome Proliferator-Activated Receptor. GAMMA.(PPAR. GAMMA.) Suppresses Colonic Epithelial Cell Turnover and Colon Carcinogenesis Through Inhibition of the. BETA.-Catenin/T Cell Factor (TCF) Pathway. Journal of pharmacological sciences. 2008; 106(4):627-38.
[53] Girnun GD, Smith WM, Drori S, et al. APC-dependent suppression of colon carcinogenesis by PPARγ. Proceedings of the National Academy of Sciences. 2002; 99(21):13771-6.
[54] Moschetta A. Nuclear receptors and cholesterol metabolism in the intestine. Atherosclerosis Supplements. 2015; 17:9-11.
[55] Schultz JR, Tu H, Luk A, et al. Role of LXRs in control of lipogenesis. Genes & development. 2000; 14(22):2831-8.
[56] Collins JL, Fivush AM, Watson MA, et al. Identification of a nonsteroidal liver X receptor agonist through parallel array synthesis of tertiary amines. Journal of medicinal chemistry. 2002; 45(10):1963-6.
[57] Chao EY, Caravella JA, Watson MA, et al. Structure-guided design of N-phenyl tertiary amines as transrepression-selective liver X receptor modulators with anti-inflammatory activity. Journal of medicinal chemistry. 2008; 51(18):5758-65.
[58] Fukuchi J, Kokontis JM, Hiipakka RA, et al. Antiproliferative effect of liver X receptor agonists on LNCaP human prostate cancer cells. Cancer research. 2004; 64(21):7686-9.
[59] Makoukji J, Shackleford G, Meffre D, et al. Interplay between LXR and Wnt/β-Catenin Signaling in the Negative Regulation of Peripheral Myelin Genes by Oxysterols. The Journal of Neuroscience. 2011; 31(26):9620.
[60] Sasso GL, Bovenga F, Murzilli S, et al. Liver X receptors inhibit proliferation of human colorectal cancer cells and growth of intestinal tumors in mice. Gastroenterology. 2013; 144(7):1497-507. e13.
[61] Uno S, Endo K, Jeong Y, et al. Suppression of β-catenin signaling by liver X receptor ligands. Biochemical Pharmacology. 2009; 77(2):186-95.
[62] To SK, Zeng J-Z, Wong AS. Nur77: a potential therapeutic target in cancer. Expert opinion on therapeutic targets. 2012; 16(6):573-85.
[63] Wang W-j, Wang Y, Chen H-z, et al. Orphan nuclear receptor TR3 acts in autophagic cell death via mitochondrial signaling pathway. Nature chemical biology. 2014; 10(2):133-40.
[64] Zhao D, Qin L, Bourbon P-M, et al. Orphan nuclear transcription factor TR3/Nur77 regulates microvessel permeability by targeting endothelial nitric oxide synthase and destabilizing endothelial junctions. Proceedings of the National Academy of Sciences. 2011; 108(29):12066-71.
[65] Zhan Y, Du X, Chen H, et al. Cytosporone B is an agonist for nuclear orphan receptor Nur77. Nature Chemical Biology. 2008; 4(9):548.
[66] Pinton P, Kroemer G. Cancer therapy: altering mitochondrial properties. Nature chemical biology. 2014; 10(2):89-90.
[67] Sun Z, Cao X, Jiang M-M, et al. Inhibition of β-catenin signaling by nongenomic action of orphan nuclear receptor Nur77. Oncogene. 2012; 31(21):2653-67.
[68] Chen H, Liu Q, Li L, et al. The orphan receptor TR3 suppresses intestinal tumorigenesis in mice by downregulating Wnt signalling. Gut. 2012; 61(5):714-24.
[69] Gupta RK, Gao N, Gorski RK, et al. Expansion of adult β-cell mass in response to increased metabolic demand is dependent on HNF-4α. Genes & development. 2007; 21(7):756-69.
[70] Wang J, Cheng H, Li X, et al. Regulation of neural stem cell differentiation by transcription factors HNF4-1 and MAZ-1. Molecular neurobiology. 2013; 47(1):228-40.
[71] Lazarevich N, Shavochkina D, Fleishman D, et al. Deregulation of hepatocyte nuclear factor 4 (HNF4) as a marker of epithelial tumors progression. Exp Oncol. 2010; 32(3):167-71.
[72] Yao HS, Wang J, Zhang XP, et al. Hepatocyte nuclear factor 4α suppresses the aggravation of colon carcinoma. Molecular carcinogenesis. 2016; 55(5):458-72.
[73] Cattin AL, Le Beyec J, Barreau F, et al. Hepatocyte Nuclear Factor 4α, a Key Factor for Homeostasis, Cell Architecture, and Barrier Function of the Adult Intestinal Epithelium. Mol Cell Biol. 2009; 29(23):6294-308.
[74] Allazikani B, Hopkins AL. How many drug targets are there. Nature Reviews Drug Discovery. 2006; 5(12):993.
[75] Yamazaki K, Shimizu M, Okuno M, et al. Synergistic effects of RXRα and PPARγ ligands to inhibit growth in human colon cancer cells—phosphorylated RXRα is a critical target for colon cancer management. Gut. 2007; 56(11):1557-63.
[76] Klopper JP, Sharma V, Bissonnette R, et al. Combination PPAR and RXR Agonist Treatment in Melanoma Cells: Functional Importance of S100A2. PPAR research. 2009; 2010.
[2] Barbier O, Torra IP, Duguay Y, et al. Pleiotropic actions of peroxisome proliferator–activated receptors in lipid metabolism and atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology. 2002; 22(5):717-26.
[3] Pascual-García M, Valledor AF. Biological roles of liver X receptors in immune cells. Archivum immunologiae et therapiae experimentalis. 2012; 60(4):235-49.
[4] Wu Y, Yu D-d, Yan D-l, et al. Liver X receptor as a drug target for the treatment of breast cancer. Anti-cancer drugs. 2016; 27(5):373-82.
[5] Xiao X, Wang P, Chou K-C. Recent progresses in identifying nuclear receptors and their families. Current topics in medicinal chemistry. 2013; 13(10):1192-200.
[6] Helsen C, Claessens F. Looking at nuclear receptors from a new angle. Molecular and cellular endocrinology. 2014; 382(1):97-106.
[7] Dawson MI, Xia Z. The retinoid X receptors and their ligands. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids. 2012; 1821(1):21-56.
[8] Korzh V. Winding roots of Wnts. Zebrafish. 2008; 5(3):159-68.
[9] Sugimura R, Li L. Noncanonical Wnt signaling in vertebrate development, stem cells, and diseases. Birth Defects Research Part C: Embryo Today: Reviews. 2010; 90(4):243-56.
[10] Reya T, Clevers H. Wnt signalling in stem cells and cancer. Nature. 2005; 434(7035):843-50.
[11] Logan CY, Nusse R. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol. 2004; 20:781-810.
[12] Powell SM, Zilz N, Beazer-Barclay Y, et al. APC mutations occur early during colorectal tumorigenesis. Nature. 1992; 359(6392):235-7.
[13] Behrens J, von Kries JP, Kühl M, et al. Functional interaction of β-catenin with the transcription factor LEF-1. Nature. 1996; 382(6592):638-42.
[14] Molenaar M, Van De Wetering M, Oosterwegel M, et al. XTcf-3 transcription factor mediates β-catenin-induced axis formation in Xenopus embryos. Cell. 1996; 86(3):391-9.
[15] He T-C, Sparks AB, Rago C, et al. Identification of c-MYC as a target of the APC pathway. Science. 1998; 281(5382):1509-12.
[16] Tetsu O, McCormick F. β-Catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature. 1999; 398(6726):422-6.
[17] He L, Lu N, Dai Q, et al. Wogonin induced G1 cell cycle arrest by regulating Wnt/β-catenin signaling pathway and inactivating CDK8 in human colorectal cancer carcinoma cells. Toxicology. 2013; 312:36-47.
[18] Yang M, Li S-N, Anjum KM, et al. A double-negative feedback loop between Wnt–β-catenin signaling and HNF4α regulates epithelial–mesenchymal transition in hepatocellular carcinoma. J Cell Sci. 2013; 126(24):5692-703.
[19] Mulholland DJ, Dedhar S, Coetzee GA, et al. Interaction of nuclear receptors with the Wnt/β-catenin/Tcf signaling axis: Wnt you like to know? Endocrine reviews. 2005; 26(7):898-915.
[20] Xiao J-H, Ghosn C, Hinchman C, et al. Adenomatous polyposis coli (APC)-independent regulation of β-catenin degradation via a retinoid X receptor-mediated pathway. Journal of Biological Chemistry. 2003; 278(32):29954-62.
[21] Pálmer HG, González-Sancho JM, Espada J, et al. Vitamin D3 promotes the differentiation of colon carcinoma cells by the induction of E-cadherin and the inhibition of β-catenin signaling. The Journal of cell biology. 2001; 154(2):369-88.
[22] Cao X, Liu W, Lin F, et al. Retinoid X receptor regulates Nur77/TR3-dependent apoptosis [corrected] by modulating its nuclear export and mitochondrial targeting. Molecular and cellular biology. 2004; 24(22):9705-25.
[23] Zhang X-k. Targeting Nur77 translocation. Expert opinion on therapeutic targets. 2007; 11(1):69-79.
[24] Lin X-F, Zhao B-X, Chen H-Z, et al. RXRα acts as a carrier for TR3 nuclear export in a 9-cis retinoic acid-dependent manner in gastric cancer cells. Journal of cell science. 2004; 117(23):5609-21.
[25] Ahuja H, Szanto A, Nagy L, et al. The retinoid X receptor and its ligands: versatile regulators of metabolic function, cell differentiation and cell death. Journal of biological regulators and homeostatic agents. 2003; 17(1):29-45.
[26] Liu B, Lee K-W, Li H, et al. Combination therapy of insulin-like growth factor binding protein-3 and retinoid X receptor ligands synergize on prostate cancer cell apoptosis in vitro and in vivo. Clinical cancer research. 2005; 11(13):4851-6.
[27] de Lera ÁR, Krezel W, Rühl R. An Endogenous Mammalian Retinoid X Receptor Ligand, At Last! ChemMedChem. 2016; 11(10):1027-37.
[28] Han A, Tong C, Hu D, et al. A direct protein-protein interaction is involved in the suppression of β-catenin transcription by retinoid X receptor α in colorectal cancer cells. Cancer biology & therapy. 2008; 7(3):454-9.
[29] Dillard AC, Lane MA. Retinol increases β-catenin-RXRα binding leading to the increased proteasomal degradation of β-catenin and RXRα. Nutrition and cancer. 2007; 60(1):97-108.
[30] Zhang F, Meng F, Li H, et al. Suppression of retinoid X receptor alpha and aberrant β-catenin expression significantly associates with progression of colorectal carcinoma. European Journal of Cancer. 2011; 47(13):2060-7.
[31] Haussler MR, Haussler CA, Bartik L, et al. Vitamin D receptor: molecular signaling and actions of nutritional ligands in disease prevention. Nutrition reviews. 2008; 66(suppl 2):S98-S112.
[32] Bikle DD. Vitamin D receptor, a tumor suppressor in skin 1. Canadian journal of physiology and pharmacology. 2014; 93(5):349-54.
[33] Maestro MA, Molnár F, Mouriño A, et al. Vitamin D receptor 2016: novel ligands and structural insights. Expert Opinion on Therapeutic Patents. 2016:1-16.
[34] Ge Z, Hao M, Xu M, et al. Novel nonsecosteroidal VDR ligands with phenyl-pyrrolyl pentane skeleton for cancer therapy. European journal of medicinal chemistry. 2016; 107:48-62.
[35] Egan JB, Thompson PA, Vitanov MV, et al. Vitamin D receptor ligands, adenomatous polyposis coli, and the vitamin D receptor FokI polymorphism collectively modulate β‐catenin activity in colon cancer cells. Molecular carcinogenesis. 2010; 49(4):337-52.
[36] Larriba MJ, Ordóñez-Morán P, Chicote I, et al. Vitamin D receptor deficiency enhances Wnt/β-catenin signaling and tumor burden in colon cancer. PloS one. 2011; 6(8):e23524.
[37] Pálmer HG, Larriba MJ, García JM, et al. The transcription factor SNAIL represses vitamin D receptor expression and responsiveness in human colon cancer. Nature medicine. 2004; 10(9):917-9.
[38] Larriba MJ, Martín-Villar E, García JM, et al. Snail2 cooperates with Snail1 in the repression of vitamin D receptor in colon cancer. Carcinogenesis. 2009; 30(8):1459-68.
[39] Larriba MJ, Valle N, Pálmer HG, et al. The inhibition of Wnt/β-catenin signalling by 1α, 25-dihydroxyvitamin D3 is abrogated by Snail1 in human colon cancer cells. Endocrine-Related Cancer. 2007; 14(1):141-51.
[40] Pendas-Franco N, Aguilera O, Pereira F, et al. Vitamin D and Wnt/β-catenin pathway in colon cancer: role and regulation of DICKKOPF genes. Anticancer Research. 2008; 28(5A):2613-23.
[41] Ahearn TU, Shaukat A, Flanders WD, et al. A randomized clinical trial of the effects of supplemental calcium and vitamin D3 on the APC/β-catenin pathway in the normal mucosa of colorectal adenoma patients. Cancer Prevention Research. 2012; 5(10):1247-56.
[42] Huerta S, Irwin RW, Heber D, et al. 1alpha, 25-(OH)(2)-D (3) and its synthetic analogue decrease tumor load in theApc (min) Mouse. Cancer Research. 1(62):741-6.
[43] Xu H, Posner GH, Stevenson M, et al. ApcMIN modulation of vitamin D secosteroid growth control. Carcinogenesis. 2010; 31(8):1434-41.
[44] Polvani S, Tarocchi M, Tempesti S, et al. Peroxisome proliferator activated receptors at the crossroad of obesity, diabetes, and pancreatic cancer. World journal of gastroenterology. 2016; 22(8):2441.
[45] Reddy AT, Lakshmi SP, Reddy RC. PPARγ as a Novel Therapeutic Target in Lung Cancer. PPAR Research. 2016; 2016.
[46] Sikka S, Chen L, Sethi G, et al. Targeting PPARγ signaling cascade for the prevention and treatment of prostate cancer. PPAR research. 2012; 2012.
[47] Zhang J, Liu X, Xie XB, et al. Multitargeted bioactive ligands for PPARs discovered in the last decade. Chemical Biology & Drug Design. 2016.
[48] Liu J, Wang H, Zuo Y, et al. Functional interaction between peroxisome proliferator-activated receptor γ and β-catenin. Molecular and cellular biology. 2006; 26(15):5827-37.
[49] Moldes M, Ying Z, Morrison RF, et al. Peroxisome-proliferator-activated receptor γ suppresses Wnt/β-catenin signalling during adipogenesis. Biochemical Journal. 2003; 376(3):607-13.
[50] Lu D, Carson DA. Repression of β-catenin signaling by PPARγ ligands. European journal of pharmacology. 2010; 636(1):198-202.
[51] Guo F, Ren X, Dong Y, et al. Constitutive expression of PPARγ inhibits proliferation and migration of gastric cancer cells and down-regulates Wnt/β-Catenin signaling pathway downstream target genes TERT and ENAH. Gene. 2016; 584(1):31-7.
[52] Fujisawa T, Nakajima A, Fujisawa N, et al. Peroxisome Proliferator-Activated Receptor. GAMMA.(PPAR. GAMMA.) Suppresses Colonic Epithelial Cell Turnover and Colon Carcinogenesis Through Inhibition of the. BETA.-Catenin/T Cell Factor (TCF) Pathway. Journal of pharmacological sciences. 2008; 106(4):627-38.
[53] Girnun GD, Smith WM, Drori S, et al. APC-dependent suppression of colon carcinogenesis by PPARγ. Proceedings of the National Academy of Sciences. 2002; 99(21):13771-6.
[54] Moschetta A. Nuclear receptors and cholesterol metabolism in the intestine. Atherosclerosis Supplements. 2015; 17:9-11.
[55] Schultz JR, Tu H, Luk A, et al. Role of LXRs in control of lipogenesis. Genes & development. 2000; 14(22):2831-8.
[56] Collins JL, Fivush AM, Watson MA, et al. Identification of a nonsteroidal liver X receptor agonist through parallel array synthesis of tertiary amines. Journal of medicinal chemistry. 2002; 45(10):1963-6.
[57] Chao EY, Caravella JA, Watson MA, et al. Structure-guided design of N-phenyl tertiary amines as transrepression-selective liver X receptor modulators with anti-inflammatory activity. Journal of medicinal chemistry. 2008; 51(18):5758-65.
[58] Fukuchi J, Kokontis JM, Hiipakka RA, et al. Antiproliferative effect of liver X receptor agonists on LNCaP human prostate cancer cells. Cancer research. 2004; 64(21):7686-9.
[59] Makoukji J, Shackleford G, Meffre D, et al. Interplay between LXR and Wnt/β-Catenin Signaling in the Negative Regulation of Peripheral Myelin Genes by Oxysterols. The Journal of Neuroscience. 2011; 31(26):9620.
[60] Sasso GL, Bovenga F, Murzilli S, et al. Liver X receptors inhibit proliferation of human colorectal cancer cells and growth of intestinal tumors in mice. Gastroenterology. 2013; 144(7):1497-507. e13.
[61] Uno S, Endo K, Jeong Y, et al. Suppression of β-catenin signaling by liver X receptor ligands. Biochemical Pharmacology. 2009; 77(2):186-95.
[62] To SK, Zeng J-Z, Wong AS. Nur77: a potential therapeutic target in cancer. Expert opinion on therapeutic targets. 2012; 16(6):573-85.
[63] Wang W-j, Wang Y, Chen H-z, et al. Orphan nuclear receptor TR3 acts in autophagic cell death via mitochondrial signaling pathway. Nature chemical biology. 2014; 10(2):133-40.
[64] Zhao D, Qin L, Bourbon P-M, et al. Orphan nuclear transcription factor TR3/Nur77 regulates microvessel permeability by targeting endothelial nitric oxide synthase and destabilizing endothelial junctions. Proceedings of the National Academy of Sciences. 2011; 108(29):12066-71.
[65] Zhan Y, Du X, Chen H, et al. Cytosporone B is an agonist for nuclear orphan receptor Nur77. Nature Chemical Biology. 2008; 4(9):548.
[66] Pinton P, Kroemer G. Cancer therapy: altering mitochondrial properties. Nature chemical biology. 2014; 10(2):89-90.
[67] Sun Z, Cao X, Jiang M-M, et al. Inhibition of β-catenin signaling by nongenomic action of orphan nuclear receptor Nur77. Oncogene. 2012; 31(21):2653-67.
[68] Chen H, Liu Q, Li L, et al. The orphan receptor TR3 suppresses intestinal tumorigenesis in mice by downregulating Wnt signalling. Gut. 2012; 61(5):714-24.
[69] Gupta RK, Gao N, Gorski RK, et al. Expansion of adult β-cell mass in response to increased metabolic demand is dependent on HNF-4α. Genes & development. 2007; 21(7):756-69.
[70] Wang J, Cheng H, Li X, et al. Regulation of neural stem cell differentiation by transcription factors HNF4-1 and MAZ-1. Molecular neurobiology. 2013; 47(1):228-40.
[71] Lazarevich N, Shavochkina D, Fleishman D, et al. Deregulation of hepatocyte nuclear factor 4 (HNF4) as a marker of epithelial tumors progression. Exp Oncol. 2010; 32(3):167-71.
[72] Yao HS, Wang J, Zhang XP, et al. Hepatocyte nuclear factor 4α suppresses the aggravation of colon carcinoma. Molecular carcinogenesis. 2016; 55(5):458-72.
[73] Cattin AL, Le Beyec J, Barreau F, et al. Hepatocyte Nuclear Factor 4α, a Key Factor for Homeostasis, Cell Architecture, and Barrier Function of the Adult Intestinal Epithelium. Mol Cell Biol. 2009; 29(23):6294-308.
[74] Allazikani B, Hopkins AL. How many drug targets are there. Nature Reviews Drug Discovery. 2006; 5(12):993.
[75] Yamazaki K, Shimizu M, Okuno M, et al. Synergistic effects of RXRα and PPARγ ligands to inhibit growth in human colon cancer cells—phosphorylated RXRα is a critical target for colon cancer management. Gut. 2007; 56(11):1557-63.
[76] Klopper JP, Sharma V, Bissonnette R, et al. Combination PPAR and RXR Agonist Treatment in Melanoma Cells: Functional Importance of S100A2. PPAR research. 2009; 2010.