Expression and Potent Actions of Urocortins and Related Peptides in Cancer Therapy

Keiichi Ikeda, Katsuyoshi Tojo, Yoshinobu Manome

Abstract


After the discovery of corticotropin-releasing factor (CRF), which is a key endocrinological molecule of the hypothalamic–pituitary–adrenal axis, it has been reported that CRF is involved in stress adaptation through CRF type 1, type 2, and type 3 (CRF-R2/CRF1, CRF-R2/CRF2, and CRF-R3) receptors. A CRF-related peptide, urocortin (UCN) I, was identified followed by identification of its related peptides UCN II and III. UCN family peptides are more potent agonists than CRF on CRF receptors, especially CRF-R2, and UCN I and its related peptides are involved in stress adaptation, especially, in peripheral tissues. UCN I has various beneficial actions and is distributed in central and peripheral normal tissues, including the brain, heart, vascular cells, and endometrium. In addition, expression of UCNs was also identified in malignant cancer cells, including human glioblastoma cells, pituitary adenoma cells, hepatic carcinoma cells, gastric cancer cells, adrenocortical adenoma cells, renal clear-cell carcinoma cells, and so on. Ectopic expression of CRF sometimes causes clinically important and obvious endocrine disorders through overproduction of corticotropin, i.e., Cushing’s syndrome. However, the pathophysiological role of UCN expression in clinical cases remains to be clarified. Recent studies reported that UCN I and its related peptides have potentially antagonistic actions against the physiological properties of cancer and supporting mechanisms of carcinogenesis, indicating that the derivatives of these peptides may exert anti-cancer properties or can be used as agents for adjuvant chemotherapy. Here, this review will describe on the expression and distribution of CRF, UCN I, and related peptides, and discuss their physiological roles in normal and malignant cancer cells with consideration of usage in anti-cancer therapy.

Keywords


CRF; urocortin; cancer therapy; CRF receptors

Full Text:

 Subscribers Only

References


Vale W, Spiess J, Rivier C, Rivier J. Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and β-endorphin. Science 1981, 213: 1394-1397

Chen R, Lewis KA, Perrin MH, Vale WW. Expression cloning of a human corticotropin-releasing-factor receptor. Proceedings of the National Academy of Sciences of the United States of America 1993, 90: 8967-8971

Perrin M, Donaldson C, Chen R, Blount A, Berggren T, Bilezikjian L, Sawchenko P, Vale W. Identification of a second corticotropin-releasing factor receptor gene and characterization of a cDNA expressed in heart. Proceedings of the National Academy of Sciences of the United States of America 1995, 92: 2969-2973

Lovenberg TW, Liaw CW, Grigoriadis DE, Clevenger W, Chalmers DT, De Souza EB, Oltersdorf T. Cloning and characterization of a functionally distinct corticotropin-releasing factor receptor subtype from rat brain. Proceedings of the National Academy of Sciences of the United States of America 1995, 92: 836-840

Arai M, Assil IQ, Abou-Samra AB. Characterization of three corticotropin-releasing factor receptors in catfish: A Novel third receptor is predominantly expressed in pituitary and urophysis. Endocrinology 2001, 142: 446-454 DOI: 10.1210/en.142.1.446

Vaughan J, Donaldson C, Bittencourt J, Perrin MH, Lewis K, Sutton S, Chan R, Turnbull AV, Lovejoy D, Rivier C, Rivier J, Sawchencho PE, Vale W. Urocortin, a mammalian neuropeptide related to fish urotensin I and to corticotropin-releasing factor. Nature 1995, 378: 287-292 DOI: 10.1038/378287a0

Reyes TM, Lewis K, Perrin MH, Kunitake KS, Vaughan J, Arias CA, Hogenesch JB, Gulyas J, Rivier J, Vale WW, Sawchenko PE. Urocortin II: a member of the corticotropin-releasing factor (CRF) neuropeptide family that is selectively bound by type 2 CRF receptors. Proceedings of the National Academy of Sciences of the United States of America 2001, 98: 2843-2848 DOI: 10.1073/pnas.051626398

Lewis K, Li C, Perrin MH, Blount A, Kunitake K, Donaldson C, Vaughan J, Reyes TM, Gulyas J, Fischer W, Bilezikjian L, Rivier J, Sawchenko PE, Vale WW. Identification of urocortin III, an additional member of the corticotropin-releasing factor (CRF) family with high affinity for the CRF2 receptor. Proceedings of the National Academy of Sciences of the United States of America 2001, 98: 7570-7575 DOI: 10.1073/pnas.121165198

Hsu SY, Hsueh AJ. Human stresscopin and stresscopin-related peptide are selective ligands for the type 2 corticotropin-releasing hormone receptor. Nature Medicine 2001, 7: 605-611 DOI: 10.1038/87936

Pisarchik A, Slominski A. Molecular and functional characterization of novel CRFR1 isoforms from the skin. European Journal of Biochemistry 2004, 271: 2821-2830 DOI: 10.1111/j.1432-1033.2004.04216.x

Wu SV, Yuan PQ, Lai J, Wong K, Chen MC, Ohning GV, Taché Y. Activation of Type 1 CRH receptor isoforms induces serotonin release from human carcinoid BON-1N cells: an enterochromaffin cell model. Endocrinology 2011, 152: 126-137 DOI: 10.1210/en.2010-0997

Lovenberg TW, Chalmers DT, Liu C, De Souza EB. CRF2α and CRF2β receptor mRNAs are differentially distributed between the rat central nervous system and peripheral tissues. Endocrinology 1995, 136: 4139-4142 DOI: 10.1210/endo.136.9.7544278

Slominski A, Pisarchik A, Tobin DJ, Mazurkiewicz JE, Wortsman J. Differential expression of a cutaneous corticotropin-releasing hormone system. Endocrinology 2004, 145: 941-950 DOI: 10.1210/en.2003-0851

Żmijewski MA, Slominski AT. Emerging role of alternative splicing of CRF1 receptor in CRF signaling. Acta Biochimica Polonica 2010, 57: 1-13

Kostich WA, Chen A, Sperle K, Largent BL. Molecular identification and analysis of a novel human corticotropin-releasing factor (CRF) receptor: the CRF2γ receptor. Molecular Endocrinology 1998, 12:1077-85 DOI: 10.1210/mend.12.8.0145

Ikeda K, Akiyoshi K, Kamada M, Fujioka K, Tojo K, Manome Y. Expression of Urocortin I in Normal Tissues and Malignant Tumors. Cancer Cell & Microenvironment 2014, 1: 45-50 DOI: 10.14800/ccm.119

Chatzaki E, Euthymiadis C, Kyriaki S, Lambropoulou M, Tsaroucha A, Laftsidis P, Simopoulos K. Urocortin and corticotropin-releasing hormone receptor type 2 expression in the human gallbladder. Neuroendocrinology 2005, 82: 177-1784 DOI: 10.1159/000091979

Tezval H, Merseburger AS, Serth J, Herrmann TW, Becker JU, Jahn O, Kuczyk MA. Differential expression of urocortin in human testicular germ cells in course of spermatogenesis: role for urocortin in male fertility? Urology 2009, 73: 901-905 DOI: 10.1016/j.urology.2008.12.029

Fukuda T, Takahashi K, Suzuki T, Saruta M, Watanabe M, Nakata T, Sasano H. Urocortin 1, urocortin 3/stresscopin, and corticotropin-releasing factor receptors in human adrenal and its disorders. Journal of Clinical Endocrinology & Metabolism 2005, 90: 4671-4678 DOI: 10.1210/jc.2005-0090

Ikeda K, Tojo K, Otsubo C, Udagawa T, Hosoya T, Tajima N, Nakao K, Kawamura M. Effects of urocortin II on neonatal rat cardiac myocytes and non-myocytes. Peptides 2005, 26: 2473-2481 DOI: 10.1016/j.peptides.2005.05.021

Inada Y, Ikeda K, Tojo K, Sakamoto M, Takada Y, Tajima N. Possible involvement of corticotropin-releasing factor receptor signaling on vascular inflammation. Peptides 2009, 30: 365-372 DOI: 10.1016/j.peptides.2008.10.015

Kageyama K, Hanada K, Suda T. Differential regulation of urocortins1-3 mRNA in human umbilical vein endothelial cells. Regulatory Peptides 2009, 155: 131-138 DOI: 10.1016/j.regpep.2009.02.012

Takahashi K, Totsune K, Saruta M, Fukuda T, Suzuki T, Hirose T, Imai Y, Sasano H, Murakami O. Expression of urocortin 3/stresscopin in human adrenal glands and adrenal tumors. Peptides 2006, 27: 178-182 DOI: 10.1016/j.peptides.2005.06.017

Kageyama K, Hanada K, Suda T. Differential regulation and roles of urocortins in human adrenal H295R cells. Regulatory Peptides 2010, 162: 18-25 DOI: 10.1016/j.regpep.2010.02.006

Li C, Chen P, Vaughan J, Blount A, Chen A, Jamieson PM, Rivier J, Smith MS, Vale W. Urocortin III is expressed in pancreatic β-cells and stimulates insulin and glucagon secretion. Endocrinology 2003, 144: 3216-3224 DOI: 10.1210/en.2002-0087

Pepels PP, Spaanderman ME, Hermus AR, Lotgering FK, Sweep CG. Placental urocortin-2 and -3: endocrine or paracrine functioning during healthy pregnancy? Placenta 2010, 31: 475-481 DOI: 10.1016/j.placenta.2010.03.012

Dermitzaki E, Tsatsanis C, Minas V, Chatzaki E, Charalampopoulos I, Venihaki M, Androulidaki A, Lambropoulou M, Spiess J, Michalodimitrakis E, Gravanis A, Margioris AN. Corticotropin-releasing factor (CRF) and the urocortins differentially regulate catecholamine secretion in human and rat adrenals, in a CRF receptor type-specific manner. Endocrinology 2007, 148: 1524-1538 DOI: 10.1210/en.2006-0967

Yata A, Nakabayashi K, Wakahashi S, Maruo N, Ohara N, Maruo T. Suppression of progesterone production by stresscopin/urocortin 3 in cultured human granulosa-lutein cells. Human Reproduction 2009, 24: 1748-1753 DOI: 10.1093/humrep/dep063

Kamada M, Ikeda K, Fujioka K, Akiyama N, Akiyoshi K, Inoue Y, Hanada S, Yamamoto K, Tojo K, Manome Y. Expression of mRNAs of urocortin and corticotropin-releasing factor receptors in malignant glioma cell lines. Anticancer Research 2012, 32: 5299-5307

Ikeda K, Fujioka K, Tachibana T, Kim SU, Tojo K, Manome Y. Secretion of urocortin I by human glioblastoma cell lines, possibly via the constitutive pathway. Peptides 2015, 63: 63-70 DOI: 10.1016/j.peptides.2014.09.007

Androulidaki A, Dermitzaki E, Venihaki M, Karagianni E, Rassouli O, Andreakou E, Stournaras C, Margioris AN, Tsatsanis C. Corticotropin releasing factor promotes breast cancer cell motility and invasiveness. Molecular Cancer 2009, 8: 30 DOI: 10.1186/1476-4598-8-30

Kaprara A, Pazaitou-Panayiotou K, Kortsaris A, Chatzaki E. The corticotropin releasing factor system in cancer: expression and pathophysiological implications. Cellular and Molecular Life Sciences 2010, 67: 1293-1306 DOI: 10.1007/s00018-010-0265-2

Simopoulos C, Christodoulou E, Lambropoulou M, Tsaroucha AK, Kakolyris S, Polychronidis A, Karayiannakis AJ, Chatzaki E. Neuropeptide urocortin 1 and its receptors are expressed in the human liver. Neuroendocrinology 2009, 89: 315-326 DOI: 10.1159/000187136

Roseboom PH, Urben CM, Kalin NH. Persistent corticotropin-releasing factor1 receptor desensitization and downregulation in the human neuroblastoma cell line IMR-32. Molecular Brain Research 2001, 92: 115-127

Reubi JC, Waser B, Vale W, Rivier J. Expression of CRF1 and CRF2 receptors in human cancers. Journal of Clinical Endocrinology & Metabolism 2003, 88: 3312-3320 DOI: 10.1210/jc.2002-021853

Funasaka Y, Sato H, Ichihashi M. Expression of corticotropin releasing hormone in malignant melanoma. Annals of the New York Academy of Sciences 1999, 885: 391-393

Kageyama K, Sakihara S, Yamashita M, Takahashi K, Kawashima S, Tanabe J, Tsutaya S, Yasujima M, Suda T. A case of multiple endocrine neoplasia type II accompanied by thyroid medullary carcinoma and pheochromocytomas expressing corticotropin-releasing factor and urocortins. American Journal of the Medical Sciences 2008, 335: 398-402 DOI: 10.1097/MAJ.0b013e31815200f8

Watanuki Y, Takayasu S, Kageyama K, Iwasaki Y, Sakihara S, Terui K, Nigawara T, Suda T. Involvement of Nurr-1/Nur77 in corticotropin-releasing factor/urocortin1-induced tyrosinase-related protein 1 gene transcription in human melanoma HMV-II cells. Molecular and Cellular Endocrinology 2013, 370: 42-51 DOI: 10.1016/j.mce.2013.01.022

Akiyoshi K, Kamada M, Fujioka K, Ikeda K, Tojo K, Manome Y. Expression of mRNAs of Urocortin in the STKM-1 gastric cancer cell line. Anticancer Research 2013, 33: 5289-5294

Rodriguez JA, Huerta-Yepez S, Law IK, Baay-Guzman GJ, Tirado-Rodriguez B, Hoffman JM, Iliopoulos D, Hommes DW, Verspaget HW, Chang L, Pothoulakis C, Baritaki S. Diminished expression of CRHR2 in human colon cancer promotes tumor growth and EMT via persistent IL-6/Stat3 signaling. Cellular and Molecular Gastroenterology and Hepatology 2015, 1: 610-630 DOI: 10.1016/j.jcmgh.2015.08.001

Wilbert-Lampen U, Straube F, Trapp A, Deutschmann A, Plasse A, Steinbeck G. Effects of corticotropin-releasing hormone (CRH) on monocyte function, mediated by CRH-receptor subtype R1 and R2: a potential link between mood disorders and endothelial dysfunction? Journal of Cardiovascular Pharmacology 2006, 47: 110-116

Dämmrich J, Ormanns W, Kahaly G, Schrezenmeir J. Multiple peptide hormone producing adenocarcinoma of lung with neurotensin and CRF-like immunoreactivity. Pathology-Research and Practice 1988, 183: 670-674 DOI: 10.1016/S0344-0338(88)80051-7

Arihara Z, Sakurai K, Osaki Y, Fukazawa H, Yamada S, Inoshita N, Murakami O, Ohba K, Takahashi K. ACTH response to desmopressin in a patient with acromegaly; expression of corticotropin-releasing factor, urocortins and vasopressin V1b receptor in GH-producing pituitary adenoma. Endocrine Journal 2011, 58: 1029-1036

Florio P, De Falco G, Leucci E, Torricelli M, Torres PB, Toti P, Dell'Anna A, Tiso E, Santopietro R, Leoncini L, Petraglia F. Urocortin expression is downregulated in human endometrial carcinoma. Journal of Endocrinology 2006, 190: 99-105 DOI: 10.1677/joe.1.06726

Tezval H, Jurk S, Atschekzei F, Serth J, Kuczyk MA, Merseburger AS. The involvement of altered corticotropin releasing factor receptor 2 expression in prostate cancer due to alteration of anti-angiogenic signaling pathways. Prostate 2009, 69: 443-448 DOI: 10.1002/pros.20892

Hao Z, Huang Y, Cleman J, Jovin IS, Vale WW, Bale TL, Giordano FJ. Urocortin2 inhibits tumor growth via effects on vascularization and cell proliferation. Proceedings of the National Academy of Sciences of the United States of America 2008, 105: 3939-3944 DOI: 10.1073/pnas.0712366105

Ikeda K, Fujioka K, Manome Y, Tojo K. Clinical perspectives of urocortin and related agents for the treatment of cardiovascular disease. International Journal of Endocrinology 2012, 2012: 198628 DOI: 10.1155/2012/198628

Pozzoli G, De Simone ML, Cantalupo E, Cenciarelli C, Lisi L, Boninsegna A, Dello Russo C, Sgambato A, Navarra P. The activation of type 1 corticotropin releasing factor receptor (CRF-R1) inhibits proliferation and promotes differentiation of neuroblastoma cells in vitro via p27Kip1 protein up-regulation and c-Myc mRNA down-regulation. Molecular and Cellular Endocrinology 2015, 412: 205-215 DOI: 10.1016/j.mce.2015.05.004

Jin L, Chen J, Li L, Li C, Chen C, Li S. CRH suppressed TGFβ1-induced Epithelial-Mesenchymal Transition via induction of E-cadherin in breast cancer cells. Cellular Signaling 2014, 26: 757-765 DOI: 10.1016/j.cellsig.2013.12.017

Jin L, Zhu C, Wang X, Li C, Cao C, Yuan J, Li S. Urocortin attenuates TGFβ1-induced Snail1 and slug expressions: inhibitory role of Smad7 in Smad2/3 signaling in breast cancer cells. Journal of Cellular Biochemistry 2015, 116: 2494-2503 DOI: 10.1002/jcb.25194

Jin L, Chen C, Guo R, Wan R, Li S. Role of corticotropin-releasing hormone family peptides in androgen receptor and vitamin D receptor expression and translocation in human breast cancer MCF-7 cells. European Journal of Pharmacology 2012, 684: 27-35 DOI: 10.1016/j.ejphar.2012.03.034

Ikezoe T, Gery S, Yin D, O'Kelly J, Binderup L, Lemp N, Taguchi H, Koeffler HP. CCAAT/enhancer-binding protein δ: a molecular target of 1,25-dihydroxyvitamin D3 in androgen-responsive prostate cancer LNCaP cells. Cancer Research 2005, 65: 4762-4768 DOI: 10.1158/0008-5472.CAN-03-3619

Zhu C, Sun Z, Li C, Guo R, Li L, Jin L, Wan R, Li S. Urocortin affects migration of hepatic cancer cell lines via differential regulation of cPLA2 and iPLA2. Cellular Signaling 2014, 26: 1125-1134 DOI: 10.1016/j.cellsig.2014.02.002

Yu H, Kumar SM, Fang D, Acs G, Xu X. Nuclear orphan receptor TR3/Nur77 mediates melanoma cell apoptosis. Cancer Biology & Therapy 2007, 6: 405-412

Safe S, Jin UH, Hedrick E, Reeder A, Lee SO. Minireview: role of orphan nuclear receptors in cancer and potential as drug targets. Molecular Endocrinology 2014, 28: 157-172 DOI: 10.1210/me.2013-1291

Jin L, Zhang Q, Guo R, Wang L, Wang J, Wan R, Zhang R, Xu Y, Li S. Different effects of corticotropin-releasing factor and urocortin 2 on apoptosis of prostate cancer cells in vitro. Journal of Molecular Endocrinology 2011, 47: 219-227 DOI: 10.1530/JME-11-0048

Carlson KW, Nawy SS, Wei ET, Sadée W, Filov VA, Rezsova VV, Slominski A, Quillan JM. Inhibition of mouse melanoma cell proliferation by corticotropin-releasing hormone and its analogs. Anticancer Research 2001, 21:1173-1179

Murakami Y, Mori T, Koshimura K, Kurosaki M, Hori T, Yanaihara N, Kato Y. Stimulation by urocortin of growth hormone (GH) secretion in GH-producing human pituitary adenoma cells. Endocrine Journal 1997, 44:627-629

Wang J, Xu Y, Xu Y, Zhu H, Zhang R, Zhang G, Li S. Urocortin's inhibition of tumor growth and angiogenesis in hepatocellular carcinoma via corticotrophin-releasing factor receptor 2. Cancer Investigation 2008, 26:359-368 DOI: 10.1080/07357900701788106




DOI: http://dx.doi.org/10.18103/imr.v2i9.205

Refbacks

  • There are currently no refbacks.
Copyright 2016. All rights reserved.