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Hücre içi sinyal iletimi mekanizmalarının kanser tanı ve tedavisindeki rolü

Yıl 2013, Cilt: 35 Sayı: 2, 302 - 310, 27.06.2013

Zehra Çoban , Şefik Güran

Öz

Özet

Sinyal iletimi hücrede basit hücresel aktiviteleri organize eden, davranışını düzenleyen hücre haberleşmesi içindeki karışık kompleks sisteminin önemli bir parçasıdır. Hücre bilgi akışındaki hatalar başta kanser, otoimmünite ve diyabet gibi hastalıkların ana nedenidir. Sinyal iletimi ile ilgili metabolik fonksiyonlar genetik mutasyonlar ve tümör hücrelerinin yakın çevre problemlerinden etkilenmesinden dolayı kanser biyolojisinin en önemli konusu haline gelmiştir. Hücre sinyal iletimi detayları ile anlaşılınca, hastalıkların etkin tedavisi mümkün olacaktır. Bu bulgulara bağlı olarak ortaya konan ilk ilaç imatinib kronik myeloid lösemi tedavisine kullanılan bir protein kinaz inhibitörüdür. 1950’li yıllarda E. Krebs ve E. Fisher’in fosforilasyonu göstermesinden itibaren protein kinazlar hücre sinyal iletiminde en önemli role sahip yapılardır. Günümüzde bazı protein kinaz inhibitörleri renal kanser hücrelerinde, küçük hücreli olmayan akciğer kanserlerinde ve kolon kanserinde yaygın olarak kullanım alanı bulmuştur. Son yıllarda yapılan bilimsel çalışmalar sonucu kansere neden olduğu bulunan bir hedefe, ona artan bir özgünlükle bağlanan yeni moleküller geliştirilmiştir. Bu nedenle normal ve farklı kanser hücre modellerinde hücre sinyal iletiminde tüm bilinmeyenlerin ortaya konması kanserde yeni tedavi protokollerinin ortaya konmasında önemlidir. Yazımızda bir model olarak hücrede sinyal iletimi anlatılmakta, kanser tedavisine özgün hedeflere karşı geliştirilen yeni ilaçlar özetlenmektedir. Kanser biyolojisinin ilgi çeken bu yeni alanında ortaya çıkan bulguların ışığında gelişen yeni fırsatlar açıklanmaya çalışılmaktadır.

Anahtar sözcükler: Sinyal iletimi, kanser biyolojisi, protein kinazlar, kişisel tedavi, büyüme faktörleri, MAP kinaz yolağı, bcl-abl füzyon proteini

 

Abstract

Cell signaling is an important part of a complex system of communication that governs basic cellular activities and coordinates cell actions. Errors in cellular information processing are responsible for diseases such as cancer, autoimmunity, and diabetes. Many of the signaling pathways that are affected by genetic mutations and the tumor microenvironment have a profound effect on core metabolism, making this topic once again one of the most intense areas of research in cancer biology. By understanding cell signaling, diseases may be treated effectively. Due to these findings imatinib is the first drug used in the treatment of chronic myelogenous leukaemia as a protein kinase inhibitor. Since the discovery of protein phosphorylation by E. Krebs and E. Fisher in the 1950s, protein kinases have been recognized as major players in cell signaling. Today, some protein kinase inhibitors are widely used to treat renal cell carcinoma, non-small-cell lung cancer and colon cancer. In recent years, new biding molecules against to a target which may be the reason of carsinogenesis are identified leading to increase selectivity of particular compounds in cell signaling. So, having the all aspects of cell signaling in normal and different types of cancer cells are important for having the new treatment protocols in cancer. Herein, the cell signaling in a model and the drugs developed against to the affected targets in cell signaling had been summarized. Also the challenges due to the new findings are tried to explain in this extremely active research area in cancer biology.

Keywords: Signal tranducing, cancer biology, protein kinases, personalized treatment, growth faktors, MAP kinase pathway, bcl-abl fusion protein

Anahtar Kelimeler

Signal tranducing cancer biology protein kinases personalized treatment growth faktors MAP kinase pathway bcl-abl fusion protein

Kaynakça

  • Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P. Molecular Biology of the Cell Fifth Edition New York, 2008
  • Doğan AL, Güç D. Sinyal iletimi mekanizmaları ve kanser. Hacettepe Tıp Dergisi 2004; 35: 34-42.
  • Blume-Jensen P, Hunter T. Oncogenic kinase signalling. Nature 2001; 411: 3556
  • Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S. The protein kinase complement of the human genome. Science 2002; 298: 1912-34.
  • Vlahopoulos S, Zoumpourlis VC. JNK: a key modulator of intracellular signaling. Biochemistry (Mosc) 2004; 69: 844-54.
  • Pawson T. Regulation and targets of receptor tyrosine kinases. Eur J Cancer. 2002; 38 Suppl 5: S3-10.
  • Bublil EM, Yarden Y. The EGF receptor family: spearheading a merger of signaling and therapeutics. Curr Opin Cell Biol 2007; 19: 124-34.
  • Cho HS, Leahy DJ. Structure of the extracellular region of HER3 reveals an interdomain tether. Science 2002; 297: 1330-3.
  • Duchesne L, Tissot B, Rudd TR, Dell A, Fernig DG. N-glycosylation of fibroblast growth factor receptor 1 regulates ligand and heparan sulfate coreceptor binding. J Biol Chem 2006; 281: 27178-89.
  • Robinson CJ, Stringer SE. The splice variants of vascular endothelial growth factor (VEGF) and their receptors. J Cell Sci 2001; 114: 853-65.
  • Arighi E, Borrello MG, Sariola H. RET tyrosine kinase signaling in development and cancer. Cytokine Growth Factor Rev 2005; 16: 441-67.
  • Hirsch FR, Scagliotti GV, Langer CJ, Varella-Garcia M, Franklin WA. Epidermal growth factor family of receptors in preneoplasia and lung cancer: perspectives for targeted therapies. Lung Cancer 2003; 41: 29-42.
  • Kim JA. Targeted therapies for the treatment of cancer. Am J Surg 2003; 186: 264Van den Eynde M, Baurain JF, Mazzeo F, Machiels JP. Epidermal growth factor receptor targeted therapies for solid tumours. Acta Clin Belg 2011; 66: 10-7.
  • Burstein HJ, Elias AD, Rugo HS, Cobleigh MA, Wolff AC, Eisenberg PD, Lehman M, Adams BJ, Bello CL, DePrimo SE, Baum CM, Miller KD. Phase II study of sunitinib malate, an oral multitargeted tyrosine kinase inhibitor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol 2008; 26: 1810-6.
  • Sulkes A. Novel multitargeted anticancer oral therapies: sunitinib and sorafenib as a paradigm. Isr Med Assoc J 2010; 12: 628-32.
  • Sordella R, Bell DW, Haber DA, Settleman J. Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 2004; 305: 1163Demetri GD, Wang Y, Wehrle E, Racine A, Nikolova Z, Blanke CD, Joensuu H, von Mehren M. Imatinib plasma levels are correlated with clinical benefit in patients with unresectable/metastatic gastrointestinal stromal tumors. J Clin Oncol 2009; 27: 3141-7.
  • Steelman LS, Franklin RA, Abrams SL, Chappell W, Kempf CR, Bäsecke J, Stivala F, Donia M, Fagone P, Nicoletti F, Libra M, Ruvolo P, Ruvolo V, Evangelisti C, Martelli AM, McCubrey JA. Roles of the Ras/Raf/MEK/ERK pathway in leukemia therapy. Leukemia 2011; 25: 1080-94.
  • Shepherd C, Puzanov I, Sosman JA. B-RAF inhibitors: an evolving role in the therapy of malignant melanoma. Curr Oncol Rep 2010; 12: 146-52.
  • McCubrey JA, Milella M, Tafuri A, Martelli AM, Lunghi P, Bonati A, Cervello M, Lee JT, Steelman LS. Targeting the Raf/MEK/ERK pathway with smallmolecule inhibitors. Curr Opin Investig Drugs 2008; 9: 614-30.
  • McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Wong EW, Chang F, Lehmann B, Terrian DM, Milella M, Tafuri A, Stivala F, Libra M, Basecke J, Evangelisti C, Martelli AM, Franklin RA. Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta 2007; 1773: 1263-84.
  • Rodig SJ, Meraz MA, White JM, Lampe PA, Riley JK, Arthur CD, King KL, Sheehan KC, Yin L, Pennica D, Johnson EM Jr, Schreiber RD. Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biologic responses. Cell 1998; 93: 373-83.
  • Hebenstreit D, Horejs-Hoeck J, Duschl A. JAK/STAT-dependent gene regulation by cytokines. Drug News Perspect 2005; 18: 243-9.
  • Chang F, Lee JT, Navolanic PM, Steelman LS, Shelton JG, Blalock WL, Franklin RA, McCubrey JA. Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy. Leukemia 2003; 17: 590-603.
  • Russell RB, Breed J, Barton GJ. Conservation analysis and structure prediction of the SH2 family of phosphotyrosine binding domains. FEBS Lett 1992; 304: 15
  • Shuai K. Regulation of cytokine signaling pathways by PIAS proteins. Cell Research 2006; 16: 196-202.
  • Benekli M, Xia Z, Donohue KA, Ford LA, Pixley LA, Baer MR, Baumann H, Wetzler M. Constitutive activity of signal transducer and activator of transcription 3 protein in acute myeloid leukemia blasts is associated with short disease-free survival. Blood 2002; 99: 252-7.
  • Kozan S, Güran Ş, Bahçe M, Kaptan K, Ifran A, Atay AA, Kürekçi AE, Beyan C. Kronik miyeloproliferatif hastalık ve miyelodisplastik sendrom olgularında Jak2 V617F mutasyonu. Gülhane Tıp Dergisi 2009; 51: 137-140.
  • Lai SY, Johnson FM. Defining the role of the JAK-STAT pathway in head and neck and thoracic malignancies: implications for future therapeutic approaches. Drug Resist Updat 2010; 13: 67-78.
  • Güran Ş, Bahçe M, Beyan C, Korkmaz K, Yalçın A. P53, p15INK4B, p16INK4A and p57KIP2 mutations during the progression of chronic myeloid leukemia. Haematologia (Budap) 1998; 29: 181-93.
  • Wei G, Rafiyath S, Liu D. First-line treatment for chronic myeloid leukemia: dasatinib, nilotinib, or imatinib. J Hematol Oncol 2010; 26: 47. le Coutre P, Ottmann OG, Giles F, Kim DW, Cortes J, Gattermann N, Apperley JF, Larson RA, Abruzzese E, O'Brien SG, Kuliczkowski K, Hochhaus A, Mahon FX, Saglio G, Gobbi M, Kwong YL, Baccarani M, Hughes T, Martinelli G, Radich JP, Zheng M, Shou Y, Kantarjian H. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or -intolerant accelerated-phase chronic myelogenous leukemia. Blood 2008; 111: 1834-9.
  • Cooper JB, Cohen EE. Mechanisms of resistance to EGFR inhibitors in head and neck cancer. Head Neck 2009; 31: 1086-94.
  • Sekulić A, Hudson CC, Homme JL, Yin P, Otterness DM, Karnitz LM, Abraham RT. A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells. Cancer Res 2000; 60: 3504-13.
  • Zinkel S, Gross A, Yang E. BCL2 family in DNA damage and cell cycle control. Cell Death Differ 2006; 13: 1351-9. http://www.biocompare.com/ProductCategories/1355/Kinase-Assays.html (Erişim tarihi 13.05.2013).

Hücre içi sinyal iletimi mekanizmalarının kanser tanı ve tedavisindeki rolü

Yıl 2013, Cilt: 35 Sayı: 2, 302 - 310, 27.06.2013

Zehra Çoban , Şefik Güran

Öz

Sinyal iletimi hücrede basit hücresel aktiviteleri organize eden, davranışını düzenleyen hücre haberleşmesi içindeki karışık kompleks sisteminin önemli bir parçasıdır. Hücre bilgi akışındaki hatalar başta kanser, otoimmünite ve diyabet gibi hastalıkların ana nedenidir. Sinyal iletimi ile ilgili metabolik fonksiyonlar genetik mutasyonlar ve tümör hücrelerinin yakın çevre problemlerinden etkilenmesinden dolayı kanser biyolojisinin en önemli konusu haline gelmiştir. Hücre sinyal iletimi detayları ile anlaşılınca, hastalıkların etkin tedavisi mümkün olacaktır. Bu bulgulara bağlı olarak ortaya konan ilk ilaç imatinib kronik myeloid lösemi tedavisine kullanılan bir protein kinaz inhibitörüdür. 1950’li yıllarda E. Krebs ve E. Fisher’in fosforilasyonu göstermesinden itibaren protein kinazlar hücre sinyal iletiminde en önemli role sahip yapılardır. Günümüzde bazı protein kinaz inhibitörleri renal kanser hücrelerinde, küçük hücreli olmayan akciğer kanserlerinde ve kolon kanserinde yaygın olarak kullanım alanı bulmuştur. Son yıllarda yapılan bilimsel çalışmalar sonucu kansere neden olduğu bulunan bir hedefe, ona artan bir özgünlükle bağlanan yeni moleküller geliştirilmiştir. Bu nedenle normal ve farklı kanser hücre modellerinde hücre sinyal iletiminde tüm bilinmeyenlerin ortaya konması kanserde yeni tedavi protokollerinin ortaya konmasında önemlidir. Yazımızda bir model olarak hücrede sinyal iletimi anlatılmakta, kanser tedavisine özgün hedeflere karşı geliştirilen yeni ilaçlar özetlenmektedir. Kanser biyolojisinin ilgi çeken bu yeni alanında ortaya çıkan bulguların ışığında gelişen yeni fırsatlar açıklanmaya çalışılmaktadır.

Anahtar Kelimeler

Sinyal iletimi kanser biyolojisi protein kinazlar kişisel tedavi büyüme faktörleri MAP kinaz yolağı bcl-abl füzyon proteini

Kaynakça

  • Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P. Molecular Biology of the Cell Fifth Edition New York, 2008
  • Doğan AL, Güç D. Sinyal iletimi mekanizmaları ve kanser. Hacettepe Tıp Dergisi 2004; 35: 34-42.
  • Blume-Jensen P, Hunter T. Oncogenic kinase signalling. Nature 2001; 411: 3556
  • Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S. The protein kinase complement of the human genome. Science 2002; 298: 1912-34.
  • Vlahopoulos S, Zoumpourlis VC. JNK: a key modulator of intracellular signaling. Biochemistry (Mosc) 2004; 69: 844-54.
  • Pawson T. Regulation and targets of receptor tyrosine kinases. Eur J Cancer. 2002; 38 Suppl 5: S3-10.
  • Bublil EM, Yarden Y. The EGF receptor family: spearheading a merger of signaling and therapeutics. Curr Opin Cell Biol 2007; 19: 124-34.
  • Cho HS, Leahy DJ. Structure of the extracellular region of HER3 reveals an interdomain tether. Science 2002; 297: 1330-3.
  • Duchesne L, Tissot B, Rudd TR, Dell A, Fernig DG. N-glycosylation of fibroblast growth factor receptor 1 regulates ligand and heparan sulfate coreceptor binding. J Biol Chem 2006; 281: 27178-89.
  • Robinson CJ, Stringer SE. The splice variants of vascular endothelial growth factor (VEGF) and their receptors. J Cell Sci 2001; 114: 853-65.
  • Arighi E, Borrello MG, Sariola H. RET tyrosine kinase signaling in development and cancer. Cytokine Growth Factor Rev 2005; 16: 441-67.
  • Hirsch FR, Scagliotti GV, Langer CJ, Varella-Garcia M, Franklin WA. Epidermal growth factor family of receptors in preneoplasia and lung cancer: perspectives for targeted therapies. Lung Cancer 2003; 41: 29-42.
  • Kim JA. Targeted therapies for the treatment of cancer. Am J Surg 2003; 186: 264Van den Eynde M, Baurain JF, Mazzeo F, Machiels JP. Epidermal growth factor receptor targeted therapies for solid tumours. Acta Clin Belg 2011; 66: 10-7.
  • Burstein HJ, Elias AD, Rugo HS, Cobleigh MA, Wolff AC, Eisenberg PD, Lehman M, Adams BJ, Bello CL, DePrimo SE, Baum CM, Miller KD. Phase II study of sunitinib malate, an oral multitargeted tyrosine kinase inhibitor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol 2008; 26: 1810-6.
  • Sulkes A. Novel multitargeted anticancer oral therapies: sunitinib and sorafenib as a paradigm. Isr Med Assoc J 2010; 12: 628-32.
  • Sordella R, Bell DW, Haber DA, Settleman J. Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 2004; 305: 1163Demetri GD, Wang Y, Wehrle E, Racine A, Nikolova Z, Blanke CD, Joensuu H, von Mehren M. Imatinib plasma levels are correlated with clinical benefit in patients with unresectable/metastatic gastrointestinal stromal tumors. J Clin Oncol 2009; 27: 3141-7.
  • Steelman LS, Franklin RA, Abrams SL, Chappell W, Kempf CR, Bäsecke J, Stivala F, Donia M, Fagone P, Nicoletti F, Libra M, Ruvolo P, Ruvolo V, Evangelisti C, Martelli AM, McCubrey JA. Roles of the Ras/Raf/MEK/ERK pathway in leukemia therapy. Leukemia 2011; 25: 1080-94.
  • Shepherd C, Puzanov I, Sosman JA. B-RAF inhibitors: an evolving role in the therapy of malignant melanoma. Curr Oncol Rep 2010; 12: 146-52.
  • McCubrey JA, Milella M, Tafuri A, Martelli AM, Lunghi P, Bonati A, Cervello M, Lee JT, Steelman LS. Targeting the Raf/MEK/ERK pathway with smallmolecule inhibitors. Curr Opin Investig Drugs 2008; 9: 614-30.
  • McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Wong EW, Chang F, Lehmann B, Terrian DM, Milella M, Tafuri A, Stivala F, Libra M, Basecke J, Evangelisti C, Martelli AM, Franklin RA. Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta 2007; 1773: 1263-84.
  • Rodig SJ, Meraz MA, White JM, Lampe PA, Riley JK, Arthur CD, King KL, Sheehan KC, Yin L, Pennica D, Johnson EM Jr, Schreiber RD. Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biologic responses. Cell 1998; 93: 373-83.
  • Hebenstreit D, Horejs-Hoeck J, Duschl A. JAK/STAT-dependent gene regulation by cytokines. Drug News Perspect 2005; 18: 243-9.
  • Chang F, Lee JT, Navolanic PM, Steelman LS, Shelton JG, Blalock WL, Franklin RA, McCubrey JA. Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy. Leukemia 2003; 17: 590-603.
  • Russell RB, Breed J, Barton GJ. Conservation analysis and structure prediction of the SH2 family of phosphotyrosine binding domains. FEBS Lett 1992; 304: 15
  • Shuai K. Regulation of cytokine signaling pathways by PIAS proteins. Cell Research 2006; 16: 196-202.
  • Benekli M, Xia Z, Donohue KA, Ford LA, Pixley LA, Baer MR, Baumann H, Wetzler M. Constitutive activity of signal transducer and activator of transcription 3 protein in acute myeloid leukemia blasts is associated with short disease-free survival. Blood 2002; 99: 252-7.
  • Kozan S, Güran Ş, Bahçe M, Kaptan K, Ifran A, Atay AA, Kürekçi AE, Beyan C. Kronik miyeloproliferatif hastalık ve miyelodisplastik sendrom olgularında Jak2 V617F mutasyonu. Gülhane Tıp Dergisi 2009; 51: 137-140.
  • Lai SY, Johnson FM. Defining the role of the JAK-STAT pathway in head and neck and thoracic malignancies: implications for future therapeutic approaches. Drug Resist Updat 2010; 13: 67-78.
  • Güran Ş, Bahçe M, Beyan C, Korkmaz K, Yalçın A. P53, p15INK4B, p16INK4A and p57KIP2 mutations during the progression of chronic myeloid leukemia. Haematologia (Budap) 1998; 29: 181-93.
  • Wei G, Rafiyath S, Liu D. First-line treatment for chronic myeloid leukemia: dasatinib, nilotinib, or imatinib. J Hematol Oncol 2010; 26: 47. le Coutre P, Ottmann OG, Giles F, Kim DW, Cortes J, Gattermann N, Apperley JF, Larson RA, Abruzzese E, O'Brien SG, Kuliczkowski K, Hochhaus A, Mahon FX, Saglio G, Gobbi M, Kwong YL, Baccarani M, Hughes T, Martinelli G, Radich JP, Zheng M, Shou Y, Kantarjian H. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or -intolerant accelerated-phase chronic myelogenous leukemia. Blood 2008; 111: 1834-9.
  • Cooper JB, Cohen EE. Mechanisms of resistance to EGFR inhibitors in head and neck cancer. Head Neck 2009; 31: 1086-94.
  • Sekulić A, Hudson CC, Homme JL, Yin P, Otterness DM, Karnitz LM, Abraham RT. A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells. Cancer Res 2000; 60: 3504-13.
  • Zinkel S, Gross A, Yang E. BCL2 family in DNA damage and cell cycle control. Cell Death Differ 2006; 13: 1351-9. http://www.biocompare.com/ProductCategories/1355/Kinase-Assays.html (Erişim tarihi 13.05.2013).
Toplam 33 adet kaynakça vardır.

Ayrıntılar

Birincil Dil Türkçe
Bölüm Derlemeler
Yazarlar

Zehra Çoban

Şefik Güran

Yayımlanma Tarihi 27 Haziran 2013
Yayımlandığı Sayı Yıl 2013Cilt: 35 Sayı: 2

Kaynak Göster

AMA Çoban Z, Güran Ş. Hücre içi sinyal iletimi mekanizmalarının kanser tanı ve tedavisindeki rolü. CMJ. Haziran 2013;35(2):302-310.