Dokument

Zusammenfassung:
Neuroendokrine Tumore stellen auch heute noch sowohl ein diagnostisches als auch therapeutisches Problem dar, weswegen weiterhin intensive Forschung notwendig ist, um Patienten mit dieser Erkrankung eine höhere Chance auf Heilung zu bieten. PPARγ-Agonisten wie Pioglitazon werden klinisch bereits in der Diabetes-Therapie eingesetzt. Es gibt allerdings Daten, die sowohl auf antikanzerogene als auch auf kanzerogene Effekte dieser Wirkstoffgruppe hinweisen. Daher wurde in dieser Arbeit die Wirkung von Pioglitazon auf das Proteom von Bon-1-Zellen untersucht, einer humanen neuroendokrinen Pankreaskarzinom-Zelllinie. Es zeigte sich, dass Pioglitazon-Behandlung in Bon-1-Zellen zu einer vermehrten Spaltung von HSP 90 führt. HSP 90 ist ein molekulares Chaperon, das eine Schlüsselrolle in vielen Zell-Signalwegen spielt und so den Eintritt der Zelle in die Apoptose verhindern kann. Ebenso ist es maßgeblich an der Entwicklung und Aufrechterhaltung derjenigen Eigenschaften von Tumorzellen beteiligt, die zu malignem Wachstum führen. Es musste jedoch festgestellt werden, dass die vermehrte Spaltung von HSP 90 anscheinend nicht zu einer signifikanten Abnahme der Gesamtmenge an HSP 90 führt, und deswegen keine Regulation von Proteinen in HSP-90-beeinflussten Signalwegen nachgewiesen werden konnte. Weiterhin konnte gezeigt werden, dass eine Inkubation von Bon-1-Zellen mit Pioglitazon zu einer Verminderung der intrazellulären Menge an CgA und SgII führt. Dieser Effekt wird nicht durch eine verminderte Expression, sondern durch eine verstärkte Sekretion erzielt. Der gleiche Effekt wurde durch Lankat-Buttgereit et al. in einer mit Pdcd4-si-RNA-transfizierten Bon-1-Zelllinie nachgewiesen. In beiden Fällem schien die gesteigerte Sekretion sowohl durch eine vermehrte Expression der Proprotein-Convertase 1 (PC1) als auch durch eine vermehrte Aktivierung der Kinase Akt, reguliert über den PI3-Kinase-Weg, bedingt zu sein. Übereinstimmend hiermit wurde in dieser Arbeit nachgewiesen, dass Pioglitazon in Bon-1-Zellen zu erniedrigten Pdcd4-Spiegeln und infolgedessen zur Aktivierung von Akt, zu gesteigerter PC1-Expression und hierdurch zu vermehrter CgA- und SgII-Sekretion führt. CgA dient als Serummarker für neuroendokrine Tumore und PC1 ist in erhöhten Mengen in verschiedenen Tumorarten zu finden. SgII ist das Vorläuferprotein von Secretoneurin (SN) und wird durch PC1 zu diesem prozessiert. SN spielt eine Rolle bei der Hypoxie-induzierten Neovaskularisation in ischämischen Erkrankungen und soliden Tumoren. Erhöhte PC1-Spiegel unter Pioglitazon-Behandlung mögen jedoch auch zur antidiabetischen Wirkung von Pioglitazon beitragen, indem es zu einer vermehrten Prozessierung von Proinsulin und Proglucagon zu Insulin und dem insulinotrop wirkenden Glucagon-like-Peptide-1 (GLP-1) kommt. Die erzielten Ergebnisse geben weiteren Anlass zu der Auffassung, dass der klinische Einsatz von Pioglitazon erneut reevaluiert werden sollte.

Bibliographie / References

1. Kitakata H, Nemoto-Sasaki Y, Takahashi Y, Kondo T, Mai M, Mukaida N (2002) Essential roles of tumor necrosis factor receptor p55 in liver metastasis of intrasplenic administration of colon 26 cells. Cancer Res 62(22):6682-7
2. Khatib AM, Fallavollita L, Wancewicz EV, Monia BP, Brodt P (2002 a) Inhibition of hepatic endothelial E-selectin expression by C-raf antisense oligonucleotides blocks colorectal carcinoma liver metastasis. Cancer Res 62(19):5393-8
3. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):57-70. Review.
4. Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, Skene AM, Tan MH, Lefèbvre PJ, Murray GD, Standl E, Wilcox RG, Wilhelmsen L, Betteridqe J, Birkeland K, Golay A, Heine RJ, Korányi L, Laakso M, Mokán M, Norkus A, Pirags V, Podar T, Scheen A, Scherbaum W, Schernthaner G, Schmitz O, Skrha J, Smith U, Taton J, PROactive investigators (2005) Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial in macroVascular Events): a randomised controlled trial. Lancet 366:1279-89
5. Salomone OA, Elliot PM, Calvino R, Holt D, Kaski JC (1996) Plasma immunoreactive endothelin concentration correlates with severity of coronary artery disease in patients with stable angina pectoris and normal ventricular function. J Am Coll Cardiol 28:14-19
6. Carinci F, Lo Muzio L, Piattelli A, Rubini C, Chiesa F, Ionna F, Palmieri A, Maiorano E, Pastore A, Laino G, Dolci M, Pezzetti F (2005) Potential markers of tongue tumor progression selected by cDNA microarray. Int J Immunopathol Pharmacol 18(3):513-24
7. Vignati S, Albertini V, Rinaldi A, Kwee I, Riva C, Oldrini R, Capella C, Bertoni F, Carbone GM, Catapano CV (2006) Cellular and molecular consequences of peroxisome proliferator-activated receptor-gamma activation in ovarian cancer cells. Neoplasia 8:851-61
8. Usmani SZ, Bona R, Li Z (2009) 17 AAG for HSP 90 inhibtion in cancer – from bench to bedside. Curr Mol Med 9(5):654-64. Review.
9. Pérez-Tenorio G, Stål O; Southeast Sweden Breast Cancer Group (2002) Activation of AKT/PKB in breast cancer predicts a worse outcome among endocrine treated patients.
10. Palamarchuk A, Efanov A, Maximov V, Aqeilan RI, Croce CM, Pekarsky Y (2005) Akt phosphorylates and regulates Pdcd4 tumor suppressor protein. Cancer Res 65(24):11282-6
11. Kirchmair R, Egger M, Walter DH, Eisterer W, Niederwanger A, Woell E, Nagl M, Pedrini M, Murayama T, Frauscher S, Hanley A, Silver M, Brodmann M, Sturm W, Fischer-Colbrie R, Losordo DW, Patsch JR, Schratzberger P (2004 a) Secretoneurin, an Angiogenic Neuropeptide, Induces Postnatal Vasculogenesis. Circulation 110:1121-7
12. Ramos-Nino ME, MacLean CD, Littenberg B (2007) Association between cancer Prevalence and use of thiazolidinediones: results fromm the Vermont Diabetes Information System. BMC Med 5: 17
13. Chang AJ, Song DH, Wolfe MM (2006) Attenuation of peroxisom proliferator-activated receptor gamma (PPARgamma) mediates gastrin-stimulated colorectal cancer cell proliferation. J Biol Chem 281:14700-10
14. Jansen AP, Camalier CE, Stark C, Colburn NH (2004) Characterization of programmed 58 cell death 4 in multiple human cancers reveals a novel enhancer of drug sensitivity. Mol Cancer Ther 3(2):103-10
15. Meterissian S, Brodt P (2005) Charakterisieren of the host proinflammatory response to tumor cells during the initial stages of liver metastasis. Am J Pathol 167(3):749-59
16. Nikou GC, Lygidakis NJ, Toubanakis C, Pavlatos S, Tseleni-Balafouta S, Giannatou E, Mallas E, Safioleas M (2005) Current diagnosis and treatment of gastrointestinal carcinoids in a series of 101 patients: the significance of serum chromogranin-A, somaostatin receptor scintigraphy and somatostatin analogues. Hepatogastroenterology 52(63):731-41
17. Szcezeblowska D (2007) Diagnostics and treatment of neuroendocrine tumors of the digestive tract in the light of the present standards. Pol Merkur Lekarski 22(131):437- 41. Review. Polish.
18. Nissen SE, Wolski K (2007) Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 356:2457-71
19. Jansen AP, Camalier CE, Colburn NH (2005) Epidermal expression of the translation inhibitor programmed cell death 4 suppresses tumorigenesis. Cancer Res 65(14):6034- 41
20. Yano M, Naito Z, Tanaka S, Asano G (1996) Expression and roles of heat shock proteins in human breast cancer. Jpn J Cancer Res 87(9):908-15
21. Chattopadhyay N, Singh DP, Heese O, Godbole MM, Sinohara T, Black PM, Brown EM (2000) Expression of peroxisome proliferator-activated receptors (PPARS) in human astrocytic cells: PPAR gamma agonists as inducers of apoptosis. J Neurosci Res 61:67-74
22. gene expression in 3T3-L1 and human adipocytes. FASEB J 15:215-20
23. Orskov C (1992) Glucagon-like peptide-1, a new hormone of the entero-insular axis.
24. Liu Y, Meng Y, Liu H, Li J, Fu J, Chen X (2006) Growth inhibition and differentiation induced by peroxisome proliferator activated receptor gamma ligand rosiglitazone in human melanoma cell line a375. Med Oncol 23:393-402
25. Zhao C, Wang E (2004) Heat shock protein 90 suppresses tumor necrosis factor alpha induced apoptosis by preventing the cleavage of Bid in NIH3T3 fibroblasts. Cell Signal 16(3):313-21
26. Neckers L (2007) Heat shock protein 90: the cancer chaperone. J Biosci 32(3):517-30. Review. 60
27. Iwaki M, Matsuda M, Maeda N, Funahashi T, Matsuzawa Y, Makishima M, Shimomura I (2003) " Induction of adiponectin, a fat-derived antidiabetic and antiatherogenic factor, by nuclear receptors. Diabetes 52(7):1655-63
28. Castrillo A, Diaz-Guerra MJ, Hortelano S, Martin-Sanz P, Bosca L (2000) Inhibition of IkappaB kinase and IkappaB phorphorylation by 15-deoxy-delta(12,14)-prostaglandin J(2) in activated murine macrophages. Mol Cell Biol 20:1692-98
29. Takahashi H, Fujita K, Fujisawa T, Yonemitsu K, Tomimoto A, Ikeda I, Yoneda M, Masuda T, Schaefer K, Saubermann LJ, Shimamura T, Saitoh S, Tachibana M, Wada K, Nakagama H, Nakajima A (2006) Inhibition of peroxisome proliferator-activated receptor gamma activity in esophageal carcinoma cells results in a drastic decrease of invasive properties.Cancer Sci 97:854-860
30. Chen YL, Law PY, Loh HH (2005) Inhibition of PI3K/Akt signaling: an emerging paradigm for targeted cancer therapy. Curr Med Chem Anticancer Agents 5(6):575-89
31. Martelli ML, Iuliano R, Le Pera I, Sama I, Monaco C, Cammarota S, Kroll T, Chiariotti L, Santoro M, Fusco A (2002) Inhibitory effects of peroxisome proliferator-activated receptor gamma on thyroid carcinoma cell growth. J Clin Endocrinol Metab 87:4728-35
32. von Wichert G, Jehle PM, Hoeflich A, Koschnick S, Dralle H, Wolf E, Wiedenmann B, Boehm BO, Adler G, Seufferlein T (2000) Insulin-like growth factor-I is an autocrine regulator of chromogranin A secretion and growth in human neuronendocrine tumor cells. Cancer Res 60(16):4573-81.
33. Seto-Young D, Avtanski D, Strizhevsky M, Parikh G, Patel P, Kaplun J, Holcomb K, Rosenwaks Z, Poretsky L (2007) Interactions among peroxisome proliferator activated receptor-gamma, insulin signaling pathways, and steroidogenic acute regulatory protein in human ovarian cells. J Clin Endocrinol Metab. 92(6):2232-9
34. Schmitt E, Gehrmann M, Brunet M, Multhoff G, Garrido C (2007) Intracellular and extracellular functions of heat shock proteins: repercussion in cancer therapy. J Leukoc Biol 81(1):15-27. Epub 2006 Aug 24. Review.
35. Zhang H, Ozaki I, Mizuta T, Hamajima H, Yasutake T, Eguchi Y, Ideguchi H, Yamamoto K, Matsuhashi S. (2006) Involvement of programmed cell death 4 in transforming growth factor-beta1-induced apoptosis in human hepatocellular carcinoma.
36. Elnemr A, Ohta T, Iwata K, Ninomia I, Fushida S, Nishimura G Kitagawa H, Kayahara 57 colon cancer in patients with diabetes. J Clin Oncol 25(2):57-8
37. Lankat-Buttgereit B, Müller S, Schmidt H, Parhofer KG, Gress TM, Göke R (2008) Knockdown of Pdcd4 results in induction of proprotein convertase 1/3 and potent secretion of chromogranin A and secretogranin II in a neuroendocrine cell line. Biol Cell 100(12):703-15
38. Yu DS, Hsieh DS, Chang SY (2003) Modulation of prostate carcinoma cell growth and apoptosis by chromogranin A. J Urol 170(5):2031-5
39. Gustafsson BI, Kidd M, Modlin IM (2008) Neuroendocrine tumors of the diffuse neuroendocrine system. Curr Opin Oncol 20(1):1-12
40. neuropeptide secretoneurin acts as a direct angiogenic cytokine in vitro and in vivo. Circulation 109(6):777-83
41. Palmer CNA, Hsu MH, Griffin KJ, Johnson EF (1995) Novel sequence determinants in peroxisome proliferator signaling. J Biol Chem 270(27):16114-121
42. Lankat-Buttgereit B, Gregel C, Knolle A, Hasilik A, Arnold R, Göke R (2004) Pdcd4 inhibits growth of tumor cells by suppression of carbonic anhydrase type II. Mol Cell Endocrinol 214(1-2):149-53
43. Han S, Roman J (2007) Peroxisome proliferator-activated receptor gamma: a novel target for cancer therapeutics? Anticancer Drugs 18(3):237-44
44. Chen F, Wang M, O`Connor JP, He M, Tripathi T, Harrison LE (2003) Phosphorylation of PPARγ via active ERK1/2 leads to its physical association with p65 and inhibition of NF-κB. J Cell Biochem 90(4):732-44
45. Osaki M, Oshimura M, Ito H (2004) PI3K-Akt pathway: Its function and alterations in human cancer. Apoptosis 9: 667-76
46. Hamblin M, Chang L, Fan Y, Zhang J, Chen YE (2009): PPARs and the cardiovascular system. Antioxid Redox Signal 11(6):1415-52
47. Sertznig P, Seifert M, Tilgen W, Reichsrath J (2007) Present concepts and future outlook: function of peroxisome proliferator-activated receptors (PPARs) for pathogenesis, progression, and therapy of cancer. J Cell Physiol 212(1):1-12
48. Hoflehner J, Eder U, Laslop A, Seidah NG, Fischer-Colbrie R, Winkler H (1995) Processing of secretogranin II by prohormone convertases: importance of PC1 in generation of secretoneurin. FEBS Lett 60(3):294-8
49. Scopsi L, Gullo M, Rilke F, Martin S, Steiner DF (1995) Proprotein convertases (PC1/PC3 and PC2) in normal and neoplastic human tissues: their use as markers of neuroendocrine differentiation. J Clin Endocrinol Metab 80:294–301
50. Khatib AM, Kontogiannea M, Fallavollita L, Jamison B, Meterissian S, Brodt P (1999) Rapid induction of cytokine and E-selectin expression in the liver in response to metastatic tumor cells. Cancer Res 59(6):1356-61
51. Scamuffa N, Siegfried G, Bontemps Y, Ma L, Basak A, Cherel G, Calvo F, Seidah NG, Khatib AM (2008) Selective inhibition of proprotein convertases represses the metastazic potential of human colorectal tumor cells. Clin Invest 118(1):352-63
52. Tanno S, Yanagawa N, Habiro A, Koizumi K, Nakano Y, Osanai M, Mizukami Y, Okumura T, Testa JR, Kohgo Y (2004) Serine/threonine kinase AKT is frequently activated in human bile duct cancer and is associated with increased radioresistance. Cancer Res 64(10):3486-90
53. Teboul L, Febbraio M, Gaillard D, Amri EZ, Silverstein R, Grimaldi PA (2001) Structural and functional characterization of the mouse fatty acid translocase promotor: activation during adipose differentiation. J Biochem 360:305-12
54. Taupenot L, Harper KL, O'Connor DT (2003) The chromogranin-secretogranin family.
55. Lehrke M, Lazar MA (2005) The many faces of PPARγ. Cell 123(6):993-99
56. Vivanco I, Sawyers CL (2002) The phosphatidylinositol 3-Kinsas AKT pathway in human cancer. Nat Rev Cancer 2(7):489-501
57. Radhakrishnan SK, Gartel AL (2005) The PPAR-gamma agonist pioglitazone post- transcriptionally induces p21 in PC3 prostate cancer but not in other cell lines. Cell Cycle 4:582-4
58. Steiner DF (1998) The proprotein convertases. Curr Opin Chem Biol 2:31–9
59. Steiner DF, Rouille Y, Gong Q, Martin S, Carroll R, Chan SJ (1996) The role of prohormone convertases in insulin biosynthesis: evidence for inherited defects in their action in man and experimental animals. Diabetes Metab 22:94–104
60. Whitesell L, Bagatell R, Falsey R (2003) The stress response: implications for the clinical developement of hsp90 inhibitors. Curr Cancer Drug Targets 3(5):349-58.
61. Quinn CE, Hamilton PK, Lockhart CJ, McVeigh GE (2008) Thiazolidinediones: effects on insulin resistance and the cardiovascular system. Br J Pharmacol 153:636-45
62. Kim SW, Choi OK, Chang MS, Shin CS, Park KS, Kim SY (2008) Thiazolidinediones inhibit the growth of PC12 cells both in vitro and in vivo. Biochem Biophys Res Commun 371(2):197-202
63. Smith U, Gogg S, Johansson A, Olausson T, Rotter V, Svalstadt B (2001) Thiazolinediones (PPARgamma agonists) but not PPAR-alpha agonists increase IRS-2
64. Yu S, Reddy JK (2007) Transcription coactivators for peroxisome proliferator-activated receptors. Biochimica et Biophysica Acta 1771(8):936-51
65. Yu J, Qiao L, Zimmermann L, Ebert MP, Zhang H, Lin W, Rocken C, Malfertheimer P, Farrell GC (2006) Troglitazone inhibits tumor growth in hepatocellular carcinoma in 65 vitro and in vivo. Hepatology 43:134-43
66. Nakashima M, Nie Y, Li QL, Friedmann TC (2001) Up-regulation of splenic prohormone convertases PC1 and PC2 in diabetic rats. Regul Pept 102(2-3):135-45
67. Pearl LH, Prodromou C, Workman P (2008) The hsp90 molecular chaperone: an open and shut case for treatment. Biochem J 410(3):439-53. Review.
68. Tzimas GN, Chevet E, Jenna S, Nguyên DT, Khatib AM, Marcus V, Zhang Y, Chrétien M, Seidah N, Metrakos P (2005) Abnormal expression and processing of the proprotein convertases PC1 and PC2 in human colorectal liver metastases. BMC Cancer 17(5):149
69. Walcher D, Marx N (2006) Glitazone 2006 – ein Update. Journal für Kardiologie 13:140-143
70. Zhu X, Zhou A, Dey A, Norrbom C, Carroll R, Zhang C, Laurent V, Lindberg I, Ugleholdt R, Holst J J, Steiner DF (2002) Disruption of PC1/3 expression in mice causes dwarfism and multiple neuroendocrine peptide processing defects. Proc Natl Acad Sci USA 99:10293–8
71. Zhu X., Orci L, Carroll R, Norrbom C, Ravazzola M, Steiner DF (2002) Severe block in processing of proinsulin to insulin accompanied by elevation of des-64,65 proinsulin intermediates in islets of mice lacking prohormone convertase 1/3. Proc Natl Acad Sci USA 99:10299–304
72. Yang HS, Jansen AP, Komar AA, Zheng X, Merrick WC, Costes S, Lockett SJ, Sonenberg N, Colburn NH (2003) The transformation suppressor Pdcd4 is a novel eukaryotic translation initiation factor 4A binding protein that inhibits translation. Mol Cell Biol 23(1):26-37
73. Khatib AM, Siegfried G, Chrétien M, Metrakos P, Seidah NG (2002 b) Proprotein convertases in tumor progression and malignancy: novel targets in cancer therapy. Am J Pathol 160(6):1921-35
74. Nemenoff RA, Weiser-Evans M, Winn RA (2008) Activation and Molecular Targets of Peroxisome Proliferator-Activated Receptor-γ Ligands in Lung Cancer. PPAR Res 2008:156875
75. Staal SP (1987) Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2: amplification of AKT1 in a primary human gastric adenocarcinoma.
76. Nie Y, Nakashima M, Brubaker PL, Li QL, Perfetti R, Jansen E, Zambre Y, Pipeleers D, Friedman TC (2000) Regulation of pancreatic PC1 and PC2 associated with increased glucagon-like peptide 1 in diabetic rats. J Clin Invest 105(7):955-65
77. Hamberg M, Svensson J, Samuelsson B (1975) Thromboxanes: a new group of biologically active compounds derived from prostaglandin endoperoxides. Proc Natl Acad Sci USA 72:2994-98
78. Okuno A, Tamemoto H, Tobe K, Ueki K, Mori Y, Iwamoto K, Umesono K, Akanuma Y, Fujiwara T, Horikoshi H, Yazaki Y, Kadowaki T (1998) Troglitazone increases the number of small adipocytes without change of white adipose tissue mass in obese Zucker rats. J Clin Invest 101:1354-61
79. Hutton JC, O'Rahilly S (1997) Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat Genet 16:303–6

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