Regulation of bombesin-stimulated cyclooxygenase-2 expression in prostate cancer cells

BMC Molecular Biology

Mark R Hellmich¹  Kirk Ives²  Celia Chao¹  Xiaodong Wen² 

[1] Sealy Center for Cancer Cell Biology, Univ. of Texas Medical Branch, 301 Univ. Blvd., Galveston, TX 77555, USA;Department of Surgery, Univ. of Texas Medical Branch, 301 Univ. Blvd., Galveston, TX 77555, USA

关键词: hormone-refractory;    neuroendocrine differentiation;    prostate cancer;    signal transduction;    gastrin-releasing peptide receptor;   

Others  :  1129281
DOI  :  10.1186/1471-2199-12-29

 received in 2011-02-15, accepted in 2011-07-11,  发布年份 2011

【 摘 要 】

Background

Cyclooxygenase-2 (COX-2) and the bombesin (BBS)-like peptide, gastrin-releasing peptide (GRP), have been implicated in the progression of hormone-refractory prostate cancer; however, a mechanistic link between the bioactive peptide and COX-2 expression in prostate cells has not been made.

Results

We report that BBS stimulates COX-2 mRNA and protein expression, and the release of prostaglandin E₂ from the GRP receptor (GRPR)-positive, androgen-insensitive prostate cancer cell line, PC-3. BBS-stimulated COX-2 expression is mediated, in part, by p38^MAPK and PI3 kinase (PI3K)/Akt pathways, and blocked by a GRPR antagonist. The PI3K/Akt pathway couples GRPR to the transcription factor, activator protein-1 (AP-1), and enhanced COX-2 promoter activity. Although BBS stimulates nuclear factor-kappaB (NF-κB) in PC-3, NF-κB does not regulate GRPR-mediated COX-2 expression. The p38^MAPK pathway increases BBS-stimulated COX-2 expression by slowing the degradation of COX-2 mRNA. Expression of recombinant GRPR in the androgen-sensitive cell line LNCaP is sufficient to confer BBS-stimulated COX-2 expression via the p38^MAPK and PI3K/Akt pathways.

Conclusions

Our study establishes a mechanistic link between GRPR activation and enhanced COX-2 expression in prostate cancer cell lines, and suggests that inhibiting GRPR may, in the future, provide an effective therapeutic alternative to non-steroidal anti-inflammatory drugs for inhibiting COX-2 in patients with recurrent prostate cancer.

【 授权许可】

   
2011 Wen et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

【 参考文献 】

• [1]di Sant'Agnese PA, de Mesy Jensen KL, Ackroyd RK: Calcitonin, katacalcin, and calcitonin gene-related peptide in the human prostate. An immunocytochemical and immunoelectron microscopic study. Arch Pathol Lab Med 1989, 113(7):790-796.
• [2]Iwamura M, Wu G, Abrahamsson PA, di Sant'Agnese PA, Cockett AT, Deftos LJ: Parathyroid hormone-related protein is expressed by prostatic neuroendocrine cells. Urology 1994, 43(5):667-674.
• [3]Vashchenko N, Abrahamsson PA: Neuroendocrine differentiation in prostate cancer: implications for new treatment modalities. Eur Urol 2005, 47(2):147-155.
• [4]Gupta S, Srivastava M, Ahmad N, Bostwick DG, Mukhtar H: Over-expression of cyclooxygenase-2 in human prostate adenocarcinoma. Prostate 2000, 42(1):73-78.
• [5]Rubio J, Ramos D, Lopez-Guerrero JA, Iborra I, Collado A, Solsona E, Almenar S, Llombart-Bosch A: Immunohistochemical expression of Ki-67 antigen, cox-2 and Bax/Bcl-2 in prostate cancer; prognostic value in biopsies and radical prostatectomy specimens. Eur Urol 2005, 48(5):745-751.
• [6]Wang W, Bergh A, Damber JE: Cyclooxygenase-2 expression correlates with local chronic inflammation and tumor neovascularization in human prostate cancer. Clin Cancer Res 2005, 11(9):3250-3256.
• [7]Cohen BL, Gomez P, Omori Y, Duncan RC, Civantos F, Soloway MS, Lokeshwar VB, Lokeshwar BL: Cyclooxygenase-2 (COX-2) expression is an independent predictor of prostate cancer recurrence. Int J Cancer 2006, 119(5):1082-1087.
• [8]Pruthi RS, Derksen JE, Moore D: A pilot study of use of the cyclooxygenase-2 inhibitor celecoxib in recurrent prostate cancer after definitive radiation therapy or radical prostatectomy. BJU Int 2004, 93(3):275-278.
• [9]Smith MR, Manola J, Kaufman DS, Oh WK, Bubley GJ, Kantoff PW: Celecoxib versus placebo for men with prostate cancer and a rising serum prostate-specific antigen after radical prostatectomy and/or radiation therapy. J Clin Oncol 2006, 24(18):2723-2728.
• [10]Dandekar DS, Lokeshwar BL: Inhibition of cyclooxygenase (COX)-2 expression by Tet-inducible COX-2 antisense cDNA in hormone-refractory prostate cancer significantly slows tumor growth and improves efficacy of chemotherapeutic drugs. Clin Cancer Res 2004, 10(23):8037-8047.
• [11]Gupta S, Adhami VM, Subbarayan M, MacLennan GT, Lewin JS, Hafeli UO, Fu P, Mukhtar H: Suppression of prostate carcinogenesis by dietary supplementation of celecoxib in transgenic adenocarcinoma of the mouse prostate model. Cancer Res 2004, 64(9):3334-3343.
• [12]Narayanan BA, Narayanan NK, Pttman B, Reddy BS: Adenocarcina of the mouse prostate growth inhibition by celecoxib: downregulation of transcription factors involved in COX-2 inhibition. Prostate 2006, 66(3):257-265.
• [13]Guo YS, Cheng JZ, Jin GF, Gutkind JS, Hellmich MR, Townsend CM Jr: Gastrin stimulates cyclooxygenase-2 expression in intestinal epithelial cells through multiple signaling pathways. Evidence for involvement of ERK5 kinase and transactivation of the epidermal growth factor receptor. J Biol Chem 2002, 277(50):48755-48763.
• [14]Hla T, Neilson K: Human cyclooxygenase-2 cDNA. Proc Natl Acad Sci USA 1992, 89(16):7384-7388.
• [15]Hussain T, Gupta S, Mukhtar H: Cyclooxygenase-2 and prostate carcinogenesis. Cancer Lett 2003, 191(2):125-135.
• [16]Kroog GS, Jensen RT, Battey JF: Mammalian bombesin receptors. Med Res Rev 1995, 15(5):389-417.
• [17]Logothetis C, Hoosein N: The inhibition of the paracrine progression of prostate cancer as an approach to early therapy of prostatic carcinoma. J Cell Biochem Suppl 1992, 16H:128-134.
• [18]Aprikian AG, Cordon-Cardo C, Fair WR, Reuter VE: Characterization of neuroendocrine differentiation in human benign prostate and prostatic adenocarcinoma. Cancer 1993, 71(12):3952-3965.
• [19]Sun B, Halmos G, Schally AV, Wang X, Martinez M: Presence of receptors for bombesin/gastrin-releasing peptide and mRNA for three receptor subtypes in human prostate cancers. Prostate 2000, 42(4):295-303.
• [20]Pinski J, Halmos G, Schally AV: Somatostatin analog RC-160 and bombesin/gastrin-releasing peptide antagonist RC-3095 inhibit the growth of androgen-independent DU-145 human prostate cancer line in nude mice. Cancer Lett 1993, 71(1-3):189-196.
• [21]Plonowski A, Schally AV, Varga JL, Rekasi Z, Hebert F, Halmos G, Groot K: Potentiation of the inhibitory effect of growth hormone-releasing hormone antagonists on PC-3 human prostate cancer by bombesin antagonists indicative of interference with both IGF and EGF pathways. Prostate 2000, 44(2):172-180.
• [22]Sehgal I, Thompson TC: Neuropeptides induce Mr 92,000 type IV collagenase (matrix metalloprotease-9) activity in human prostate cancer cell lines. Cancer Res 1998, 58(19):4288-4291.
• [23]Hoosein NM, Logothetis CJ, Chung LW: Differential effects of peptide hormones bombesin, vasoactive intestinal polypeptide and somatostatin analog RC-160 on the invasive capacity of human prostatic carcinoma cells. J Urol 1993, 149(5):1209-1213.
• [24]Lacoste J, Aprikian AG, Chevalier S: Focal adhesion kinase is required for bombesin-induced prostate cancer cell motility. Mol Cell Endocrinol 2005, 235(1-2):51-61.
• [25]Nagakawa O, Ogasawara M, Fujii H, Murakami K, Murata J, Fuse H, Saiki I: Effect of prostatic neuropeptides on invasion and migration of PC-3 prostate cancer cells. Cancer Lett 1998, 133(1):27-33.
• [26]Levine L, Lucci JA, Pazdrak B, Cheng JZ, Guo YS, Townsend CM Jr, Hellmich MR: Bombesin stimulates nuclear factor kappa B activation and expression of proangiogenic factors in prostate cancer cells. Cancer Res 2003, 63(13):3495-3502.
• [27]Baroni A, Perfetto B, Canozo N, Braca A, Farina E, Melito A, De Maria S, Carteni M: Bombesin: A possible role in wound repair. Peptides 2008, 29(7):1157-1166.
• [28]Corral RS, Iniguez MA, Duque J, Lopez-Perez R, Fresno M: Bombesin induces cyclooxygenase-2 expression through the activation of the nuclear factor of activated T cells and enhances cell migration in Caco-2 colon carcinoma cells. Oncogene 2007, 26(7):958-969.
• [29]Hohla F, Schally AV, Kanashiro CA, Buchholz S, Baker B, Kannadka C, Moder A, Aigner E, Datz C, Halmos G: Growth inhibition of non-small-cell lung carcinoma by BN/GRP antagonist is linked with suppression of K-Ras, COX-2, and pAkt. Proc Natl Acad Sci USA 2007, 104(47):18671-18676.
• [30]Damge C, Hajri A: Effect of the gastrin-releasing peptide antagonist BIM 26226 and lanreotide on an acinar pancreatic carcinoma. Eur J Pharmacol 1998, 347(1):77-86.
• [31]Kang YJ, Mbonye UR, DeLong CJ, Wada M, Smith WL: Regulation of intracellular cyclooxygenase levels by gene transcription and protein degradation. Prog Lipid Res 2007, 46(2):108-125.
• [32]Klein T, Shephard P, Kleinert H, Komhoff M: Regulation of cyclooxygenase-2 expression by cyclic AMP. Biochim Biophys Acta 2007, 1773(11):1605-1618.
• [33]Mestre JR, Rivadeneira DE, Mackrell PJ, Duff M, Stapleton PP, Mack-Strong V, Maddali S, Smyth GP, Tanabe T, Daly JM: Overlapping CRE and E-box promoter elements can independently regulate COX-2 gene transcription in macrophages. FEBS Lett 2001, 496(2-3):147-151.
• [34]Newton R, Kuitert LM, Bergmann M, Adcock IM, Barnes PJ: Evidence for involvement of NF-kappaB in the transcriptional control of COX-2 gene expression by IL-1beta. Biochem Biophys Res Commun 1997, 237(1):28-32.
• [35]Janelle ME, Gravel A, Gosselin J, Tremblay MJ, Flamand L: Activation of monocyte cyclooxygenase-2 gene expression by human herpesvirus 6. Role for cyclic AMP-responsive element-binding protein and activator protein-1. J Biol Chem 2002, 277(34):30665-30674.
• [36]Siebenlist U, Franzoso G, Brown K: Structure, regulation and function of NF-kappa B. Annu Rev Cell Biol 1994, 10:405-455.
• [37]Baldwin AS Jr: The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol 1996, 14:649-683.
• [38]Reile H, Armatis PE, Schally AV: Characterization of high-affinity receptors for bombesin/gastrin releasing peptide on the human prostate cancer cell lines PC-3 and DU-145: internalization of receptor bound 125I-(Tyr4) bombesin by tumor cells. Prostate 1994, 25(1):29-38.
• [39]Wasilenko WJ, Cooper J, Palad AJ, Somers KD, Blackmore PF, Rhim JS, Wright GL Jr, Schellhammer PF: Calcium signaling in prostate cancer cells: evidence for multiple receptors and enhanced sensitivity to bombesin/GRP. Prostate 1997, 30(3):167-173.
• [40]Guo YS, Hellmich MR, Wen XD, Townsend CM Jr: Activator protein-1 transcription factor mediates bombesin-stimulated cyclooxygenase-2 expression in intestinal epithelial cells. J Biol Chem 2001, 276(25):22941-22947.
• [41]Niesporek S, Kristiansen G, Thoma A, Weichert W, Noske A, Buckendahl AC, Jung K, Stephan C, Dietel M, Denkert C: Expression of the ELAV-like protein HuR in human prostate carcinoma is an indicator of disease relapse and linked to COX-2 expression. Int J Oncol 2008, 32(2):341-347.
• [42]Dixon DA, Kaplan CD, McIntyre TM, Zimmerman GA, Prescott SM: Post-transcriptional control of cyclooxygenase-2 gene expression. The role of the 3'-untranslated region. J Biol Chem 2000, 275(16):11750-11757.
• [43]Jang BC, Sanchez T, Schaefers HJ, Trifan OC, Liu CH, Creminon C, Huang CK, Hla T: Serum withdrawal-induced post-transcriptional stabilization of cyclooxygenase-2 mRNA in MDA-MB-231 mammary carcinoma cells requires the activity of the p38 stress-activated protein kinase. J Biol Chem 2000, 275(50):39507-39515.
• [44]Ristimaki A, Garfinkel S, Wessendorf J, Maciag T, Hla T: Induction of cyclooxygenase-2 by interleukin-1 alpha. Evidence for post-transcriptional regulation. J Biol Chem 1994, 269(16):11769-11775.
• [45]Shao J, Sheng H, Inoue H, Morrow JD, DuBois RN: Regulation of constitutive cyclooxygenase-2 expression in colon carcinoma cells. J Biol Chem 2000, 275(43):33951-33956.
• [46]Inoue H, Nanayama T, Hara S, Yokoyama C, Tanabe T: The cyclic AMP response element plays an essential role in the expression of the human prostaglandin-endoperoxide synthase 2 gene in differentiated U937 monocytic cells. FEBS Lett 1994, 350(1):51-54.
• [47]Tazawa R, Xu XM, Wu KK, Wang LH: Characterization of the genomic structure, chromosomal location and promoter of human prostaglandin H synthase-2 gene. Biochem Biophys Res Commun 1994, 203(1):190-199.
• [48]The Leuprolide Study Group: Leuprolide versus diethylstilbestrol for metastatic prostate cancer. N Engl J Med 1984, 311(20):1281-1286.
• [49]di Sant'Agnese PA: Neuroendocrine differentiation in prostatic carcinoma: an update on recent developments. Ann Oncol 2001, 12(Suppl 2):S135-140.
• [50]Cuttitta F, Carney DN, Mulshine J, Moody TW, Fedorko J, Fischler A, Minna JD: Bombesin-like peptides can function as autocrine growth factors in human small-cell lung cancer. Nature 1985, 316(6031):823-826.