Regulation of p53 by siRNA in radiation treated cells: Simulation studies

Puszyński, K. ; Jaksik, R. ; Świerniak, A.

International Journal of Applied Mathematics and Computer Science, Tome 22 (2012) no. 4, pp. 1011-1018.

Résumé

Ionizing radiation activates a large variety of intracellular mechanisms responsible for maintaining appropriate cell functionality or activation of apoptosis which eliminates damaged cells from the population. The mechanism of such induced cellular death is widely used in radiotherapy in order to eliminate cancer cells, although in some cases it is highly limited by increased cellular radio-resistance due to aberrations in molecular regulation mechanisms of malignant cells. Despite the positive correlation between the radiation dose and the number of apoptotic cancer cells, radiation has to be limited because of extensive side effects. Therefore, additional control signals whose role will be to maximize the cancer cells death-ratio while minimizing the radiation dose and by that the potential side effects are worth considering. In this work we present the results of simulation studies showing possibilities of single gene regulation by small interfering RNA (siRNA) that can increase radio-sensitivity of malignant cells showing aberrations in the p53 signaling pathway, responsible for DNA damage-dependant apoptosis. By blocking the production of the p53 inhibitor Mdm2, radiation treated cancer cells are pushed into the apoptotic state on a level normally achievable only with high radiation doses. The presented approach, based on a simulation study originating from experimentally validated regulatory events, concerns one of the basic problems of radiotherapy dosage limitations, which, as will be shown, can be partially avoided by using the appropriate siRNA based control mechanism.

Détail

Keywords: siRNA, p53, combined therapy
Mots-clés : siRNA, p53, terapia skojarzona

Bibliographie

[1] Davis, M. E. (2009). The first targeted delivery of siRNA in humans via a self-assembling, cyclodextrin polymer-based nanoparticle: From concept to clinic, Molecular Pharmacology 6(3): 659-668.

[2] Dorsett, Y. and Tuschl, T. (2009). siRNAs: Applications in functional genomics and potential as therapeutics, Nature Reviews Drug Discovery 3(4): 318-329.

[3] Fire, A., Xu, S., Montgomery, M., Kostas, S., Driver, S. and Mello, C. (1998). Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans, Nature 391(6669): 806-811.

[4] Fujarewicz, K. (2010). Planning identification experiments for cell signaling pathways: An NFkB case study, International Journal of Applied Mathematics and Computer Science 20(4): 773-780, DOI: 10.2478/v10006-010-0059-6.

[5] García, J., Silva, J., Peña, C., Garcia, V., Rodríguez, R., Cruz, M.A., Cantos, B., Provencio, M., España, P. and Bonilla, F. (2004). Promoter methylation of the PTEN gene is a common molecular change in breast cancer, Genes Chromosomes and Cancer 41(2): 117-124.

[6] Gatter, K., Brown, G., Trowbridge, I., Woolston, R. and Mason, D. (1983). Transferring receptors in human tissues: Their distribution and possible clinical relevance, Journal of Clinical Pathology 36(5): 539-545.

[7] Geva-Zatorsky, N., Rosenfeld, N., Itzkovitz, S., Milo, R., Sigal, A., Dekel, E., Yarnitzky, T., Liron, Y., Polak, P., Lahav, G. and Alon, U. (2006). Oscillations and variability in the p53 system, Molecular Systems Biology 2: 2006.0033.

[8] Giono, L. and Manfredi, J. (2007). Mdm2 is required for inhibition of cdk2 activity by p21, thereby contributing to p53-dependent cell cycle arrest, Molecular Cell Biology 27(11): 4166-4178.

[9] Goldstein, I., Marcel, V., Olivier, M., Oren, M., Rotter, V. and Hainaut, P. (2011). Understanding wild-type and mutant p53 activities in human cancer: New landmarks on the way to targeted therapies, Cancer Gene Therapy 18(1): 2-11.

[10] Hannon, G. and Rossi, J. (2004). Unlocking the potential of the human genome with RNA interference, Nature 431(7006): 371-378.

[11] Harris, S. and Levine, A. (2005). The p53 pathway: Positive and negative feedback loops, Oncogene 24(17): 2899-2908.

[12] Haupt, Y., Maya, R., Kazaz, A. and Oren, M. (1997). Mdm2 promotes the rapid degradation of p53, Nature 387(6630): 296-299.

[13] Hrstka, R., Coates, P. and Vojtesek, B. (2009). Polymorphisms in p53 and the p53 pathway: Roles in cancer susceptibility and response to treatment, Journal of Cellular and Molecular Medicine 13(3): 440-453.

[14] Kim, B., Tang, Q., Biswas, P., Xu, J., Schiffelers, R., Xie, F., Ansari, A., Scaria, P., Woodle, M., Lu, P. and Rouse, B. (2004). Inhibition of ocular angiogenesis by siRNA targeting vascular endothelial growth factor pathway genes: Therapeutic strategy for herpetic stromal keratitis, The American Journal of Pathology 165(6): 2177-2185.

[15] Kohn, K. and Pommier, Y. (2005). Molecular interaction map of the p53 and mdm2 logic elements, which control the off-on switch of p53 in response to DNA damage, Biochemical and Biophysical Research Communications 331(3): 816-827.

[16] Krawczyk, B., Rudnicka, K. and Fabianowska-Majewska, K. (2007). The effects of nucleoside analogues on promoter methylation of selected tumor suppressor genes in mcf-7 and mda-mb-231 breast cancer cell lines, Nucleosides, Nucleotides and Nucleic Acids 26(8-9): 1043-1046.

[17] Levine, A., Hu, W. and Feng, Z. (2006). The p53 pathway: What questions remain to be explored?, Cell Death and Differentiation 13(6): 1027-1036.

[18] Li, L. and Ross, A. (2007). Why is PTEN an important tumor suppressor?, Journal of Cellular Biochemistry 102(6): 1368-1374.

[19] Li, W. and Cha, L. (2007). Predicting siRNA efficiency, Cellular and Molecular Life Sciences 64(14): 1785-11792.

[20] Makinen, P., Koponen, J., Karkkainen, A., Malm, T., Pulkkinen, K., Koistinaho, J., Turunen, M. and Yla-Herttuala, S. (2006). Stable RNA interference: Comparison of u6 and h1 promoters in endothelial cells and in mouse brain, The Journal of Gene Medicine 8(4): 433-441.

[21] Overhoff, M.,Wnsche, W. and Sczakiel, G. (2004). Quantitative detection of siRNA and single-stranded oligonucleotides: Relationship between uptake and biological activity of siRNA, Nucleic Acids Research 32(21): e170.

[22] Puszynski, K., Hat, B. and Lipniacki, T. (2008). Oscillations and bistability in the stochastic model of p53 regulation, Journal of Theoretical Biology 254(2): 452-465.

[23] Ryther, R., Flynt, A., Phillips, J. and Patton, J. (2005). siRNA therapeutics: Big potential from small RNAs, Gene Therapy 12(1): 5-11.

[24] Shim, M. and Kwon, Y. (2010). Efficient and targeted delivery of siRNA in vivo, FEBS Journal 277(23): 4814-4827.

[25] Świerniak, A., Ledzewicz, U. and Schättler, H. (2003). Optimal control for a class of compartmental models in cancer chemotherapy, International Journal of Applied Mathematics and Computer Since 13(3): 357-368.

[26] Veldhoen, S., Laufer, S. D., Trampe, A. and Restle, T. (2006). Cellular delivery of small interfering RNA by a non-covalently attached cell-penetrating peptide: Quantitative analysis of uptake and biological effect, Nucleic Acids Research 34(22): 6561-6573.