title: MAP kinase pathways and calcitonin influence CD44 alternate isoform expression in prostate cancer cells.
abstract: BACKGROUND
  Dysregulated expression and splicing of cell adhesion marker CD44 is found in many types of cancer. In prostate cancer (PC) specifically, the standard isoform (CD44s) has been found to be downregulated compared with benign tissue whereas predominant variant isoform CD44v7-10 is upregulated. Mitogen-activated protein kinase pathways and paracrine calcitonin are two common factors linked to dysregulated expression and splicing of CD44 in cancer. Calcitonin has been found to increase proliferation and invasion in PC acting through the protein kinase A pathway.
  
  
  METHODS
  In androgen-independent PC with known high CD44v7-10 expression, CD44 total and CD44v7-10 RNA or protein were assessed in response to exogenous and endogenous calcitonin and to inhibitors of protein kinase A, MEK, JNK, or p38 kinase. Benign cells and calcitonin receptor-negative PC cells were also tested.
  
  
  RESULTS
  MEK or p38 but not JNK reduced CD44 total RNA by 40%-65% in cancer and benign cells. Inhibition of protein kinase A reduced CD44 total and v7-10 protein expression. In calcitonin receptor-positive cells only, calcitonin increased CD44 variant RNA and protein by 3 h and persisting to 48 h, apparently dependent on an uninhibited p38 pathway. Cells with constitutive CT expression showed an increase in CD44v7-10 mRNA but a decrease in CD44 total RNA.
  
  
  CONCLUSIONS
  The MEK pathway increases CD44 RNA, while calcitonin, acting through the protein kinase A and p38 pathway, facilitates variant splicing. These findings could be used in the formulation of therapeutic methods for PC targeting CD44 alternate splicing.
authors.affiliation: Department of Pathology, Anschutz Medical Campus, University of Colorado Denver, Aurora, Colorado, USA. Eric.Robbins@UCHSC.edu
authors.forename: Eric W
authors.initials: EW
authors.lastname: Robbins
authors.forename: Emily A
authors.initials: EA
authors.lastname: Travanty
authors.forename: Kui
authors.initials: K
authors.lastname: Yang
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Iczkowski
mesh_terms: D017398:Alternative Splicing; D000951:Antigens, Neoplasm / Q000378:metabolism*; D002116:Calcitonin / Q000494:pharmacology / Q000502:physiology*; D045744:Cell Line, Tumor; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D020033:Protein Isoforms / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D002116:Calcitonin; D017868:Cyclic AMP-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases
references.citation: Eur J Immunol. 2001 Feb;31(2):600-8
references.pmid: 11180125
references.citation: EMBO J. 2001 Aug 1;20(15):4194-203
references.pmid: 11483522
references.citation: Cancer Res. 1993 Apr 1;53(7):1516-21
references.pmid: 8453616
references.citation: Cell Signal. 2005 Aug;17(8):961-73
references.pmid: 15894169
references.citation: Mol Endocrinol. 2006 Aug;20(8):1894-911
references.pmid: 16574742
references.citation: J Pathol. 2006 Feb;208(3):401-7
references.pmid: 16369914
references.citation: Eur J Immunol. 1993 Aug;23(8):1902-9
references.pmid: 7688309
references.citation: Oncogene. 1999 Jun 3;18(22):3376-82
references.pmid: 10362358
references.citation: Int J Biochem Cell Biol. 1999 Jan;31(1):43-57
references.pmid: 10216943
references.citation: Lab Invest. 2004 Jul;84(7):894-907
references.pmid: 15107804
references.citation: J Urol. 1998 Oct;160(4):1562-6
references.pmid: 9751413
references.citation: Mol Cell Endocrinol. 2001 Jul 5;181(1-2):69-79
references.pmid: 11476942
references.citation: J Urol. 2000 Dec;164(6):2156-61
references.pmid: 11061947
references.citation: Clin Cancer Res. 2005 Aug 15;11(16):6065-74
references.pmid: 16115952
references.citation: Int J Oncol. 2007 Dec;31(6):1425-37
references.pmid: 17982669
references.citation: Eur Urol. 2006 Nov;50(5):1102-9; discussion 1109-10
references.pmid: 16413100
references.citation: Anticancer Res. 2005 May-Jun;25(3B):2075-83
references.pmid: 16158948
references.citation: J Biol Chem. 2005 Apr 15;280(15):14773-9
references.pmid: 15708859
references.citation: Eur J Cancer Prev. 2006 Feb;15(1):57-63
references.pmid: 16374231
references.citation: FEBS Lett. 2002 Sep 25;528(1-3):101-8
references.pmid: 12297287
references.citation: Biochem Biophys Res Commun. 2007 Feb 16;353(3):744-9
references.pmid: 17196171
references.citation: Int J Cancer. 2001 Jan 1;91(1):46-54
references.pmid: 11149419
references.citation: J Pathol. 2002 Jun;197(2):148-54
references.pmid: 12015737
references.citation: J Pharmacol Exp Ther. 2002 Mar;300(3):1000-7
references.pmid: 11861809
references.citation: Genes Dev. 2002 Dec 1;16(23):3074-86
references.pmid: 12464636
references.citation: Genes Dev. 2006 Jul 1;20(13):1715-20
references.pmid: 16818603
references.citation: Nat Rev Mol Cell Biol. 2003 Jan;4(1):33-45
references.pmid: 12511867
references.citation: Int J Oncol. 2007 Nov;31(5):1119-26
references.pmid: 17912438
references.citation: Anticancer Res. 2006 Jul-Aug;26(4B):2863-72
references.pmid: 16886606
references.citation: Oncol Rep. 2006 Jan;15(1):199-206
references.pmid: 16328056
references.citation: Methods. 2001 Dec;25(4):402-8
references.pmid: 11846609
references.citation: Clin Exp Metastasis. 2003;20(3):195-201
references.pmid: 12741678
references.citation: Proc Natl Acad Sci U S A. 2007 Feb 13;104(7):2519-24
references.pmid: 17284589
references.citation: Anticancer Res. 2003 Jul-Aug;23(4):3129-40
references.pmid: 12926045
references.citation: Prostate. 1992;21(2):87-97
references.pmid: 1409122
references.citation: Int J Cancer. 2005 Nov 20;117(4):551-60
references.pmid: 15929083
references.citation: Cancer Lett. 2004 Nov 25;215(2):239-47
references.pmid: 15488643
references.citation: Endocrinology. 1994 Feb;134(2):596-602
references.pmid: 8299557