ГЕНЫ ИНГИБИТОРОВ АПОПТОЗА В КАЧЕСТВЕ МИШЕНЕЙ ПРОТИВОРАКОВОЙ ТЕРАПИИ И ПРОГНОСТИЧЕСКИХ МАРКЕРОВ

DOI: https://doi.org/None

А.А. Коротаева, кандидат медицинских наук, А.В. Карпухин, доктор биологических наук Медико-генетический научный центр РАН, Российская Федерация, 115478, Москва, ул. Москворечье, д. 1 E-mail: karpukhin@med-gen.ru

Гены, кодирующие белки IAP (Inhibitor of Apoptosis Proteins), имеют повышенную экспрессию в клетках раковых опухолей различной локализации. Белки ингибиторы апоптоза IAP выполняют ряд функций, связанных с жизнеспособностью раковых клеток и их дальнейшей пролиферацией. Они ингибируют активацию каскада каспаз, предотвращая таким образом апоптоз раковых клеток. Вследствие этого гены IAP в раковых клетках являются потенциальной мишенью для терапевтического воздействия. Ингибирование активности этих генов должно приводить к активации каскада каспаз и, соответственно, к усилению чувствительности раковых клеток к апоптотическим стимулам. Благодаря этим свойствам гены семейства IAP являются перспективными терапевтическими мишенями для разработки новых средств терапии рака. Кроме того, эти гены перспективны для разработки современных прогностических маркеров развития рака и его чувствительности к химиотерапии.
Ключевые слова: 
гены ингибиторы апоптоза, таргетная терапия, прогностические маркеры

Список литературы: 
  1. Miura K., Fujibuchi W., Ishida K., Naitoh T., Ogawa H., Ando T., Yazaki N., Watanabe K., Haneda S., Shibata C. Inhibitor of apoptosis protein family as diagnostic markers and therapeutic targets of colorectal cancer. Surg Today. 2011; 41: 175–82.
  2. Zaman S., Wang R., Gandhi V. Targeting the Apoptosis Pathway in Hematologic Malignancies. Leuk Lymphoma. 2014; 55 (9): 1980–92.
  3. Hanahan D., Weinberg R.A. Hallmarks of cancer: the next generation. Cell. 2011; 144 (5): 646–74.
  4. Ramakrishnan V., Painuly U., Kimlinger T., Haug J., Rajkumar S.V., Kumar S. Inhibitor of apoptosis proteins (IAPs) as therapeutic targets in multiple myeloma (MM). Leukemia. 2014, Jan 9. doi: 10.1038/leu.2014.2.
  5. Portt L., Norman G., Clapp C., Greenwood M. Greenwood M.T. Anti-apoptosis and cell survival: A review – Biochimica et Biophysica Acta (BBA). Molecular Cell Research – Biochimica et Biophysica Acta. 2011: 238–59.
  6. Crook N., Clem R., Miller L. An apoptpsis-ingibiting bacalovirus gene with a zinc finger-like motif. J. Virol. 1993; 67: 2168–74.
  7. Wei Y., Fan T., Yu M. Inhibitor of apoptosis proteins and apoptosis. Acta Biochim. Biophys Sin. 2008; 40: 278–88.
  8. Fulda S., Vucic D. Targeting IAP proteins for therapeutic intervention in cancer. Nat Rev. Drug Discov. 2012; 1: 109–23.
  9. Huang Q., Deveraux Q.L., Maeda S., Salvesen G.S., Stennicke H.R., Hammock B.D., Reed J.C. Evolutionary conservation of apoptosis mechanisms: lepidopteran and baculoviral inhibitor of apoptosis proteins are inhibitors of mammalian caspase-9. Proc Natl. Acad. Sci. 2000; 97: 1427–32.
  10. Mannhold К., Fulda S., Carosati E. IAP antagonists: promising candidates for cancer therapy. Drug Discov. 2010: 210–9.
  11. de Almagro M.C., Vucic D. The inhibitor of apoptosis (IAP) proteins are critical regulators of signaling pathways and targets for anti-cancer therapy. Exp. Oncol. 2012; 34 (3): 200–11.
  12. Davoodi J., Lin L., Kelly J., Liston P., MacKenzie A. Neuronal apoptosisinhibitory protein does not interact with Smac and requires ATP to bind caspase-9. J. Biol. Chem. 2004; 279: 40622–8.
  13. Yan B Research progress on Livin protein: an inhibitor of apoptosis. Mol. Cell. Biochem. 2011; 357 (1–2): 39–45.
  14. Wilkinson J., Wilkinson A., Scott F., Csomos R., Salvesen G., Duckett C. Neutralization of Smac/Diablo by inhibitors of apoptosis (IAPs). A caspase-independent mechanism for apoptotic inhibition. J. Biol. Chem. 2004; 279: 51082–90.
  15. Naniche N., Sau D., Pasinelli P. In vivo and in vitro determination of cell death markers in neurons. Methods Mol. Biol. 2011; 793: 9–21.
  16. Lowe S.W., Lin A.W. Apoptosis in cancer. Carcinogenesis. 2000; 21: 485–95.
  17. Jaffer S., Orta L., Sunkara S. et al. Immunohistochemical detection of antiapoptotic protein X-linked inhibitor of apoptosis in mammary carcinoma. Hum. Pathol. 2007; 38: 864–70.
  18. Nakagawa Y., Abe S., Kurata M. et al. IAP family protein expression correlates with poor outcome of multiple myeloma patients in association with chemotherapy-induced overexpression of multidrug resistance genes. Am. J. Hematol. 2006; 81: 824–31.
  19. Mehrotra S., Languino L.R., Raskett C.M., Mercurio A.M., Dohi T., Altieri D.C. IAP regulation of metastasis. Cancer Cell. 2010; 17 (1): 53–64.
  20. Low C.G., Luk I.S.U., Lin D., Fazli L., Yang K. BIRC6 Protein, an Inhibitor of Apoptosis: Role in Survival of Human Prostate Cancer Cells. PLoS ONE. 2013; 8 (2).
  21. Che X., Yang D., Zong H., Wang J., Li X., Chen F., Chen X., Song X. Nuclear cIAP1 overexpression is a tumor stage- and grade-independent predictor of poor prognosis in human bladder cancer patients. Urol. Oncol. 2011; 30 (4): 450–6.
  22. Xiang G., Wen X., Wang H., Chen K. & Liu H. Expression of X linked inhibitor of apoptosis protein in human colorectal cancer and its correlation with prognosis. J. Surg. Oncol. 2009; 100: 708–12.
  23. Qi S., Mogi S., Tsuda H., Tanaka Y., Kozaki K., Imoto I., Inazawa J., Hasegawa S, Omura K Expression of cIAP-1 correlates with nodal metastasis in squamous cell carcinoma of the tongue. Int. J. Oral. Maxillofac Surg. 2008; 37 (11): 1047–53.
  24. Tamm I., Kornblau S.M., Segall H., Krajewski S., Welsh K., Kitada S., Scudiero D.A., Tudor G., Qui Y.H., Monks A., Andreeff M., Reed J.C. Expression and prognostic significance of IAP-family genes in human cancers and myeloid leukemias. Clin. Cancer Res. 2000; 6 (5): 1796–803.
  25. Castells M., Milhas D., Gandy C., Thibault B., Rafii A., Delord J.P., Couderc B. Microenvironment mesenchymal cells protect ovarian cancer cell lines from apoptosis by inhibiting XIAP inactivation. Cell. Death Dis. 2013; 31: 4.
  26. Augello C., Caruso L., Maggioni M., Donadon M., Montorsi M., Santambrogio R., Torzilli G., Vaira V., Pellegrini C., Roncalli M., Coggi G., Bosari S. Inhibitors of apoptosis proteins (IAPs) expression and their prognostic significance in hepatocellular carcinoma. BMC Cancer. 2009; 9: 125.
  27. Shibata T., Mahotka C., Wethkamp N., Heikaus S., Gabbert H.E., Ramp U. Disturbed expression of the apoptosis regulators XIAP, XAF1, and Smac/DIABLO in gastric adenocarcinomas. Diagn. Mol. Pathol. 2007; 16 (1): 1–8.
  28. Hiscutt E.L., Hill D.S., Martin S., Kerr R., Harbottle A., Birch-Machin M., Redfern C.P., Fulda S., Armstrong J.L., Lovat P.E. Targeting X-linked inhibitor of apoptosis protein to increase the efficacy of endoplasmic reticulum stress-induced apoptosis for melanoma therapy. J. Invest. Dermatol. 2010; 130 (9): 2250–8.
  29. Cheung C.H., Huang C.C., Tsai F.Y., Lee J.Y., Cheng S.M., Chang Y.C., Huang Y.C., Chen S.H., Chang J.Y. Survivin – biology and potential as a therapeutic target in oncology. Onco Targets Ther. 2013; 6: 1453–62.
  30. Kempkensteffen C., Hinz S., Christoph F., Krause H., Koellermann J., Magheli A., Schrader M., Schostak M., Miller K., Weikert S. Expression of the apoptosis inhibitor livin in renal cell carcinomas: correlations with pathology and outcome. Tumour Biol. 2007; 28 (3): 132–8.
  31. Zhou J., Yuen N.K., Zhan Q., Velazquez E.F., Murphy G.F., Giobbie-Hurder A., Hodi F.S. Immunity to the melanoma inhibitor of apoptosis protein (ML-IAP; livin) in patients with malignant melanoma. Cancer Immunol. Immunother. 2012; 61 (5): 655–65.
  32. Wang T.S., Ding Q.Q., Guo R.H., Shen H., Sun J., Lu K.H., You S.H., Ge H.M., Shu Y.Q., Liu P. Expression of livin in gastric cancer and induction of apoptosis in SGC-7901 cells by shRNA-mediated silencing of livin gene. Biomed. Pharmacother. 2010; 64 (5): 333–8.
  33. Chen X., Wang T., Yang D., Wang J., Li X., He Z., Chen F., Che X., Song X. Expression of the IAP protein family acts cooperatively to predict prognosis in human bladder cancer patients. Oncol. Lett. 2013; 5 (4): 1278–84.
  34. Xi R.C., Biao W.S. and Gang Z.Z. Significant elevation of survivin and livin expression in human colorectal cancer: inverse correlation between expression and overall survival. Onkologie. 2011; 34: 428–32.
  35. Li W.Q., Li X.L., Wang G.P. and Fu B: Gene expression of livin and survivin in adult patients with acute lymphoblastic leukemia and its clinical significance. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2011; 19: 921–5.
  36. Bo-Young Oh, Ryung-Ah Lee, Kwang Ho Kim. siRNA targeting Livin decreases tumor in a xenograft model for colon cancer. World J. Gastroenterol. 2011; 17 (20): 2563–71.
  37. Pirollo K.F., Chang E.H. Targeted delivery of small interfering RNA: approaching effective cancer therapies. Cancer Res. 2008; 68: 1247–50.
  38. Bavykin A.S., Korotaeva A.A., Poyarkov S.V., Syrtsev A.V., Tjulandin S.A., Karpukhin A.V. Double siRNA-targeting of cIAP2 and LIVIN results in synergetic sensitization of HCT-116 cells to oxaliplatin treatment. OncoTargets and Therapy. 2013; 6: 1333–40.
  39. Jin H., Lee T. Cell cycle-dependent expression of cIAP2 at G2/M phase contributes to survival during mitotic cell cycle arrest. Biochem J. 2006; 399 (2): 335–42.
  40. Probst B.L., Liu L., Ramesh V., Li L., Sun H., Minna J.D., Wang L. Smac mimetics increase cancer cell response to chemotherapeutics in a TNF-α-dependent manner. 2010; 10: 1645–54.
  41. Dineen S.P., Roland C.L., Greer R., Carbon J.G., Toombs J.E., Gupta P., Bardeesy N., Sun H., Williams N., Minna J.D., Brekken R.A. Smac mimetic increases chemotherapy response and improves survival in mice with pancreatic cancer. Cancer Res. 2010; 70 (7): 2852–61.

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