Nf-Kappa B Sinyal Yolu ve Kanserde Potansiyel Terapotik Yaklaşımlar

Hücrenin hayatta kalmasıyla ilgili hücre içi yollar, gelişim ve nörodejeneratif bozukluklar sırasında nöronal fizyolojiyi düzenler. Bu süreçlerde önemli bir rolle ortaya çıkan yollardan biri Nüklear Faktör-κB (NF-κB) sinyal yolağıdır. Bu yolağın aktivitesi, NF-κB transkripsiyon faktörlerinin nüklear translokasyonuna ve anti-apoptotik gen ekspresyonunun düzenlenmesine yol açar. Farklı uyaranlar, farklı hücre içi kademeler (kanonik, kanonik olmayan ve atipik) yoluyla bu yolağı aktive ederek NF-κB transkripsiyon faktörlerinin belirli dimerlerinin translokasyonuna katkıda bulunabilir ve bu dimerlerden her biri farklı genlerin transkripsiyonunu düzenleyebilir. Son çalışmalar, bu yolun aktivasyonunun, hücrenin hayatta kalması veya nöronal dejenerasyon gibi zıt yanıtları düzenlediğini göstermiştir. Bu bariz çelişkili etkiler, yolak uyarısı, hücrelerin kaynağı veya hücresel bağlam gibi koşullara bağlıdır.

Anahtar Kelimeler:

NF-κB, NF-κB sinyal yolu, Kanser

Nf-Kappa B Signaling Pathway and Potential Therapeutic Approaches in Cancer

Intracellular pathways involved in cell survival regulate neuronal physiology during development and neurodegenerative disorders. One of the pathways that appears to play an important role in these processes is the nuclear factor-κB signaling pathway. The activity of this pathway leads to nuclear translocation of NF-κB transcription factors and regulation of anti-apoptotic gene expression. Different stimuli can contribute to the translocation of certain dimers of NF-κB transcription factors by activating the pathway through different intracellular cascades (canonical, non-canonical and atypical), and each of these dimers can regulate the transcription of different genes. Recent studies have shown that activation of this pathway regulates opposite responses such as cell survival or neuronal degeneration. These obvious contradictory effects are dependent on conditions such as pathway stimulation, source of cells or cellular context.

Keywords:

NF-κB, NF-κB Signal Patchway, Cancer,

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Zhang, L, Zhao, J, Gurkar, A, Niedernhofer, L.J, Robbins, P.D, Methods to quantify the nf-κb pathway during senescence, Methods İn Molecular Biology, 2019, 1896, 231-250.
Jimi, E, Fei, H, Nakatomi, C, NF-κB signaling regulates physiological and pathological chondrogenesis, International Journal of Molecular Science, 2019, 20(24), 6275.
Friedmann, M.D, Narasimamurthy, R, Xia, Y, Myskiw, C, Soda, Y, Verma, I.M, Targeting NF-κB in glioblastoma: A therapeutic approach, Science Advances, 2016, 2(1), e1501292.
Luo, J.L, Kamata, H, Karin, M, IKK/NF-κB Signaling: Balancing Life And Death A New Approach To Cancer Therapy. The Journal of Clinical Investigation. 2005, 115, 2625–2632.
Dutta, J, Fan, Y, Gupta, N, Fan, G, Gelinas, C, Current insights into the regulation of programmed cell death by NF-κB. Oncogene, 2006, 25, 6800–6816.
Su, S, Chen, J, Yao, H, Liu, J, Yu, S, Lao, L, et al., CD10+GPR77+ Cancer-Associated Fibroblasts Promote Cancer Formation And Chemoresistance By Sustaining Cancer Stemness, Cell, 2018, 172, 841–56.E16.
Tilborghs, S, Corthouts, J, Verhoeven, Y, Arias, D, Rolfo C, Trinh XB, van Dam PA, 2017, The role of nuclear factor-kappa b signaling in human cervical cancer, Critical Reviews in Oncology/Hematology, 2017, 120, 141-150.
Baud, V, Karin, M, Is NF-κB a good target for cancer therapy? Hopes and pitfalls, Nature Reviews Drug Discovery volume, 2009, 8, 33–40.
Dolcet, X, Llobet, D, Pallares, J, Guiu, X.M, NF-kB in development and progression of human cancer, Virchows Arch, 2005, 446(5), 475-82.
Nakanishi, C, Toi, M, Nuclear factor-κB İnhibitors As Sensitizers To Anticancer Drugs, Nature Reviews Cancer, 2005, 5, 297–309.
Hayden, M.S, Ghosh, S, NF-kappaB, the first quarter-century: Remarkable progress and outstanding questions. Genes&Development, 2012, 26, 203–234.
Mitchell, S, Vargas, J, Hoffmann, A, Signaling via the nfκb system, Wires System Biology And Medicine, 2016, doi.org/10.1002/wsbm.1331.
Herrington, F.D, Carmody, R.J, Goodyear, C.S, Modulation of NF-kappaB signaling as a therapeutic target in autoimmunity. Journal of Biomolecular Screen, 2016, 21, 223–242.
Ghosh, S, Hayden, M.S, Ghosh, G, New regulators of NF-kappaB in inflammation, Nature Reviews Immunology, 2008, 8, 837-848.
Zhang, Q, Lenardo, M.J, Baltimore, D, 30 Years of NF-kappaB: a blossoming of relevance to human pathobiology, Cell, 2017, 168, 37–57.
Oeckinghaus, A.A, Ghosh, S, The NF-κB family of transcription factors and ıts regulation, Cold Spring Harbor Perspectives in Biology, 2009, p.a000034.
Sun, S.C, The non-canonical NF-κB pathway in immunity and inflammation, Nature Reviews Immunology, 2017, 17(9), 545-558. doi: 10.1038/nri.2017.52.
Hayden, M.S, Ghosh, S, Signaling to NF-Κb, Genes&Development, 2008, 18, 2195-2224.
Dobrzanski, P, Ryseck, R.P, Bravo, R, Differential interaction of rel-nf-kb complexes with ıkba determine pools of constituve and inducible nf kb activity, EMBO Journal, 1994, 19, 4608-4616.
Cartwright, T, Perkins, N.D, Wilson, C.L, NFKB1: a suppressor of inflammation, ageing and cancer. The FEBS Journal, 2016, 283, 1812–22.
Keats, J.J, Fonseca, R, Chesi, M, Schop, R, Baker, A, Chng, W.J, et al., Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma, Cancer Cell, 2007, 12, 131–144.
Khongthong, P, Roseweir, A.K, Edwards, J, The NF-KB pathway and endocrine therapy resistance in breast cancer, Endocrine-Related Cancer, 2019, 26, 6, 10.1530/ERC-19-0087.
Demchenko, Y.N, Brents, L.A, Li, Z, Bergsagel, L.P, McGee, L.R, Kuehl, M.V, Novel inhibitors are cytotoxic for myeloma cells with NFkB inducing kinase-dependent activation of NFkB, Oncotarget, 2014, 5(12), 4554–4566.
Dejardin, E, The alternative NF-kappaB pathway from biochemistry to biology : pitfall and promises for future drug development, Biochem pharmacol, 2006, 72(9), 1161-1179.
Demchenko YN, Kuehl WM, A critical role for the NFkB pathway in multiple myeloma, Oncotarget, 2010, 1(1), 59–68.
Hoesel, B, Schmid, J.A, The complexity of NF-kappaB signaling in inflammation and cancer, Molecular Cancer, 2013, 12, 86.
Kucharczak, J, Simmons, M.J, Fan, Y, Gelinas, C, To be, or not to be: NF-kappaB is the answer–role of Rel/NF-kappaB in the regulation of apoptosis, Oncogene, 2003, 22(56), 8961-8982.
Perkins, N.D, Gilmore, T.D, Good cop, bad cop: the different faces of NF-kappaB, Cell Death Differ, 2006, 13(5), 759-772.
Perkins, N.D, Achieving transcriptional specificity with NF-kappa B, International Journal of Biochemical Cell Biology, 1997, 29 (12), 1433-1448.
Rosa, F.A, Pierce, J.W, Sonenshein, G.E, Differential regulation of the c-myc oncogene promoter by the NF-kappa B rel family of transcription factors, Molecular Cell Biology, 1994, 14(2), 1039-1044.
Verma, I.M, Stevenson, J.K, Schwarz, E.M, Van, A.D, Miyamoto, S, Rel/NF-kappa B/I kappa B family: intimate tales of association and dissociation, Genes&Development, 1995, 9(22) 2723-35.
Ramsey, K.M, Chen, W, Marion, J.D, Bergqvist, S, Komives, E.A, Exclusivity and compensation in nfkb dimer distributions and ıkb inhibition, Biochemistry, 2019, 58(21), 2555–2563.
Gershtein, E, Scherbakov, A, Platova, A, et al., Expression and activity of the nuclear transcription factor NF-carr B, its inhibitor 1kBα and protein kinase Akt1 in tumors of patients with breast cancer, Almanac of Clinical Medicine, 2010, 1, 55–60.
Karin, M, Ben, N.Y, Phosphorylation meets ubiquitination: the control of nf kappa b activity, Annual Review İmmunology, 2000, 18, 621-663.
Smyth, M.J, Dunn, G.P, Schreiber, R.D, Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity, Advences in Immunology, 2006, 90, 1-50.
Serasanambati, M, Chilakapati, S.R, Function of Nuclear Factor kappa B (NF-kB) in human diseases-A Review. South Indian Journal Of Biological Sciences, 2016, 2(4), 368-387.
Basseres, D.S, Baldwin, A.S, Nuclear factor-κB and inhibitor of kappa B kinase pathways in oncogenic initiation and progression. Oncogene, 2006, 25, 6817–30.
Karin, M, NF-κB as a critical link between inflammation and cancer. Cold Spring Harbor Perspective of Biology. 2009, 1, a000141.
Ben, N.Y, Karin, M, Inflammation meets cancer, with NF-κB as the matchmaker, Nature Immunology, 2011, 12, 715–23.
DiDonato, J.A, Mercurio, F, Karin, M, NF-κB and the link between inflammation and cancer, Immunology Reviews, 2012, 246, 379–400.
Lane, D.P, Midgley, C.A, Hupp, T.R, Lu, X, Vojtesek, B, Picksley, S.M, On the regulation of the p53 tumour suppressor, and its role in the cellular response to DNA damage, Philosophical Transaction of the Royal Society of London B Biological Sciences, 1995, 347, 83–7.
Barkett, M, Gilmore, T.D, Control of apoptosis by Rel/NF-κB transcription factors, Oncogene, 1999, 18, 6910–24.
Biswas, D.K, Cruz, A.P, Gansberger, E, Pardee, A.B, Epidermal growth factor-induced nuclear factor κB activation: a major pathway of cell-cycle progression in estrogen-receptor negative breast cancer cells, Proceeding of the National Academy of Science of the USA, 2000, 97, 8542–7.
Ainbinder, E, Revach, M, Wolstein, O, Moshonov, S, Diamant, N, Dikstein, R, Mechanism of rapid transcriptional induction of tumor necrosis factor alpha-responsive genes by NF-κB. Molecular Cellular Biology, 2002, 22, 6354–62.
Sen, R, Control of B lymphocyte apoptosis by the transcription factor NF-Κb, Immunity, 2006, 25, 871–83.
Dai, W, Wu, J, Wang, D, Wang, J, Cancer gene therapy by nf-κb-activated cancer cell-specific expression of crıspr/cas9 targeting telomeres, Springer Nature, 2020, doi.org/10.1038/s41434-020-0128-x.
Teo, H, Ghosh, S, Luesch, H, Ghosh, A, Wong, E.T, Malik, N, etal., Telomere-independent Rap1 is an IKK adaptor and regulates NF-kappaB Dependent Gene Expression, 2010, 12(8), 758-67
Chen, F, Wang, M, O’Connor, J.P, He, M, Tripathi, T, Harrison, L.E, Phosphorylation of PPARgamma via active ERK1/2 leads to its physical association with p65 and inhibition of NF-kappa beta, Journal of Cellular Biochemistry, 2003, 90, 732–744.
Disis, M.L, Immune regulation of cancer, Jornal of Clinical Oncology, 2010, 28 (29), 4531-4538.
Ryan, K.M, Ernst, M.K, Rice, N.R, Vousden, K.H, Role of NF-kappaB in p53-mediated programmed cell death, Nature, 2000, 404 (6780),: 892-897.
Gaptulbarova, K.A, Tsyganov, M.M, Pevzner, A.M, Ibragimova, M.K, Litviakov, N.V, NF-kB as a potential prognostic marker and a candidate for targeted therapy of cancer, 2020, Oncology, doi:10.32471/exp-oncology.2312-8852.vol-42-no-4.15414.
Bray, F, Ferlay, J, Soerjomataram, I, Siegel, R.L, Torre, L.A, Jemal, A, Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries, CA. A Cancer Journal for Clinicals, 2018, 68, 394-424.
Tergaonkar, V, Bottero, V, Ikawa, M, Li, Q, Verma, I.M, IkappaB kinase-independent IkappaBalpha degradation pathway: Functional NF-kappaB activity and implications for cancer therapy. Molecular and Cellular Biology, 2003, 23, 8070–8083.
Pires, B.R.B, Silva, R.C.M.C, Ferreira, G.M, Abdelhay, E, NF-kappaB: two sides of the same coin. Genes, 2018, 9(1).
Yıldırım, S, Erdoğan, A.P, Is Folfırınox Better In Primary Resected Metastatic Pancreatic Cancer? Celal Bayar Üniversitesi Sağlık Bilimleri Enstitüsü Dergisi, 2021, 8(4), 592 – 597.
Singh, S, Singh, T.G, Role of Nuclear Factor Kappa B (NF-KB) Signalling in Neurodegenerative Diseases: An Mechanistic Approach, Current Neuropharmacology, 2020, 18(10), 918–935.