Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/20227
標題: 人類粒線體NAD(P)+-依賴型蘋果酸酶在肺癌及乳癌細胞中所扮演之角色
Functional Roles of Mitochondrial NAD(P)+-Dependent-Malic Enzyme (ME2) Lung and Breast Cancer Cell Line
作者: 呂亞諭
YA YU, LU
關鍵字: 蘋果酸酶;Malic Enzyme (ME2);肺癌;乳癌;Lung cancer;Breast cancer
出版社: 生命科學系所
引用: 1. 李燕霖 (民93)。槲皮酮及其代謝產物對人類肝癌細胞株 Hep 3B 生長之抑制機轉及槲皮酮對正常大鼠初代肝細胞麩胱甘肽相關之解毒代謝與抗氧化系統之影響 (碩士論文)。取自台灣博碩士論文系統。(系統編號 093NTU05252010 ) 2. 廖雅芳 (民91)。在人類白血病細胞中人類鳥胺酸去羧化酶抑制 rottlerin 所引發之細胞凋亡機制之探討 (碩士論文)。取自台灣博碩士論文系統。(系統編號 091CSMU0543004) 3. 謝郁安 (民96)。 Protoapigenone 與 Apigenin 引發乳癌細胞 MDA-MB-231 凋亡之機轉探討(碩士論文)。取自台灣博碩士論文系統。(系統編號 096KMC05068021) 4. 張立昇 (民93)。桑色素 (Morin) 藉由細胞週期停滯及活化粒線體路徑誘導細胞凋亡進而抑制人類血癌細胞 (HL-60) 生長 (碩士論文)。取自台灣博碩士論文系統。(系統編號093CMCH0534004 ) 5. Auvinen, M., Paasinen, A., Andersson, L.C., & Holtta, E. (1992): Ornithine decarboxylase activity is critical for cell transformation. Nature. 360, 355-358. 6. Balasundaram, D. & Tyagi, A.K. (1991). Polyamine-DNA nexus: structural ramifications and biological implications. Mol Cell Biochem. 100, 129-140. 7. Bhattacharya, S., Ray, R.M., & Johnson, L.R. (2009). Role of polyamines in p53-dependent apoptosis of intestinal epithelial cells. Cell Signal. 21, 509-522. 8. Chen, V., Staub, R.E., Baggett, S., Chimmani, R., Tagliaferri, M., Cohen, I., & Shtivelman, E. (2012).Identification and analysis of the active phytochemicals from the anti-cancer botanical extract bezielle. PLoS One. 7(1), e30107. 9. Giardiello, F.M., Hamilton, S.R., Hylind, L.M., Yang, V.W., Tamez, P., & Casero, R.A. (1997). Ornithine decarboxylase and polyamines in familial adenomatous polyposis. Cancer Res. 15, 57(2),199-201. 10. Huang, C.C., Hsu, P.C., Hung, Y.C., Liao, Y.F., Liu, C.C., Hour, C.T., Kao, M.C., Tsay, G.J., Hung, H.C., & Liu, G.Y. (2005). Ornithine decarboxylase prevents methotrexate-induced apoptosis by reducing intracellular reactive oxygen species production. Apoptosis. 10, 895-907. 11. Kandil, F.E., Smith, M.A., Rogers, R.B., Pepin, M.F., Song, L.L., Pezzuto, J.M., & Seigler, D.S.(2002). Composition of a chemopreventive proanthocyanidin-rich fraction from cranberry fruits responsible for the inhibition of 12-O-tetradecanoyl phorbol-13-acetate (TPA)-induced ornithine decarboxylase (ODC) activity. J Agric Food Chem. 27, 50(5), 1063-1069. 12. Kilpelainen, P.T., Saarimies, J., Kontusaari, S.I., Jarvinen, M.J., Soler, A.P., Kallioinen, M.J. & Hietala, O.A. (2001). Abnormal ornithine decarboxylase activity in transgenic mice increases tumor formation and infertility. Int J Biochem Cell. 33, 507-520. 13. Ko, C.H., Shen, S.C., Hsu, C.S., & Chen, Y.C. (2005). Mitochondrial-dependent, reactive oxygen species-independent apoptosis by myricetin: roles of protein kinase C, cytochrome c, and caspase cascade. Biochem. Pharmacol., 69, 913-927. 14. Liu, G.Y., Hung, Y.C., Hsu, P.C., Liao, Y.F., Chang, W.H., Tsay, G.J., & Hung, H.C. (2005). Ornithine decarboxylase prevents tumor necrosis factor alpha-induced apoptosis by decreasing intracellular reactive oxygen species. Apoptosis. 10, 569-581. 15. Mangold, U. & Leberer, E. (2005). Regulation of all members of the antizyme family by antizyme inhibitor. Biochem J. 385, 21-28. 16. Manni, A., Mauger, D., Gimotty, P., & Badger, B. (1996). Prognostic influence on survival of Increased ornithine decarboxylase activity in human breast cancer. Clin Cancer Res. 2(11), 1901-1906. 17. Mohan, R.R., Challa, A., Gupta, S., Bostwick, D.C., Ahmad, N., Agarwal, R., Marengo, S.R., Amini, S.B., Paras, F., MacLennan, G.T., Resnick, M.I., & Mukhtar, H. (1999). Overexpression of ornithine decarboxylase in prostate cancer and prostatic fluid in humans. Clin. Cancer Res. 5, 143-147. 18. Nemoto, T., Kamei, S., Seyama, Y., & Kubota, S. (2001). p53 independent G(1) arrest induced by DL-alpha-difluoromethylornithine. Biochem Biophys Res Commun. 280, 848-854. 19. O''Brien, T.G. (1976). The induction of ornithine decarboxylase as an early, possibly obligatory, event in mouse skin carcinogenesis. Cancer Res. 36, 2644-2653. 20. Park, J.K., Chung, Y.M., Kang, S., Kim, J.U., Kim, Y.T., Kim, H.J., Kim, Y.H., Kim, J.S., & Yoo, Y.D. (2002). c-Myc exerts a protective function through ornithine decarboxylase against cellular insults. Mol Pharmacol. 62, 1400-1408. 21. Pegg, A.E., Madhubala, R., Kameji, T., & Bergeron, R.J. (1988). Control of ornithine decarboxylase activity in alpha-difluoromethylornithine-resistant L1210 cells by polyamines and synthetic analogues. J Biol Chem. 5;263(22), 11008-11014. 22. Ploszaj, T., Motyl, T., Zimowska, W., Skierski, J. & Zwierzchowski, L. (2000). Inhibition of ornithine decarboxylase by alpha-difluoromethylornithine induces apoptosis of HC11 mouse mammary epithelial cells. Amino Acids.19, 483-496. 23. Poulin, R., Lu, L., Ackermann, B., Bey, P., & Pegg, A.E. (1992). Mechanism of the irreversible inactivation of mouse ornithine decarboxylase by alpha-difluoromethylornithine. Characterization of sequences at the inhibitor and coenzyme binding sites. J Biol Chem. 267, 150-158. 24. Shah, N., Thomas, T., Shirahata, A., Sigal, L.H., & Thomas, T.J. (1999). Activation of nuclear factor κB by polyamines in breast cancer cells. Biochemistry. 38, 14763–14774. 25. Shantz, L.M. & Levin, V.A. (2007). Regulation of ornithine decarboxylase during oncogenic transformation: mechanisms and therapeutic potential. Amino Acids. 33, 213-223. 26. Sharma, S., Stutzman, J.D., Kelloff, G.J., & Steele, V.E. (1994). Screening of potential chemopreventive agents using biochemical markers of carcinogenesis. Cancer Res. 54, 5848-5855. 27. Zou, C., Vlastos, A.T., Yang, L., Wang, J., Nishioka, K., & Follen, M. (2002). Effects of difluoromethylornithine on growth inhibition and apoptosis in human cervical epithelial and cancerous cell lines. Gynecol Oncol. 85, 266-273. 28. Ling Li, Lisheng Wang,Liang Li, Zhiqiang Wang, Yinwei Ho, Tinisha McDonald, Tessa L. Holyoake,WenYong Chen, and Ravi Bhatia (2011). Activation of p53 by SIRT1 Inhibition Enhances Elimination of CML Leukemia Stem Cells in Combination with Imatinib. 266 Cancer Cell 21, 266–281, February 14, 2012 a2012 Elsevier Inc. 29. Peng Jiang, Wenjing Du, Anthony Mancuso, Kathryn E. Wellen & Xiaolu Yang. (2013.). Reciprocal regulation of p53 and malic enzymes modulates metabolism and senescence. doi:10.1038/nature11776. 30. Ren J-G, Seth P, Everett P, Clish CB, Sukhatme VP (2010) Induction of Erythroid Differentiation in Human Erythroleukemia Cells by Depletion of Malic Enzyme 2. PLoS ONE 5(9): e12520. doi:10.1371/journal.pone.0012520 31. Campisi, J. & d’Adda di Fagagna, F. Cellular senescence: when bad things happen to good cells. Nature Rev. Mol. Cell Biol. 8, 729–740 (2007). 32. Ben-Porath, I. & Weinberg, R. A. The signals and pathways activating cellular senescence. Int. J. Biochem. Cell Biol. 37, 961–976 (2005). 33. Hsu, R. Y. Pigeon liver malic enzyme. Mol. Cell. Biochem. 43, 3–26 (1982). 34. Chang, G. G. & Tong, L. Structure and function of malic enzymes, a new class of oxidative decarboxylases. Biochemistry 42, 12721–12733 (2003). 35. Pongratz, R. L., Kibbey, R. G., Shulman, G. I. & Cline, G. W. Cytosolic and mitochondrial malic enzyme isoforms differentially control insulin secretion. J. Biol. Chem. 282, 200–207 (2007). 36. Wellen, K. E. et al. ATP-citrate lyase links cellularmetabolismto histone acetylation.Science 324, 1076–1080 (2009). 37. Ferbeyre, G. et al. PML is induced by oncogenic ras and promotes premature senescence. Genes Dev. 14, 2015–2027 (2000). 38. Pearson, M. et al. PML regulates p53 acetylation and premature senescence induced by oncogenic Ras. Nature 406, 207–210 (2000). 39. Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D. & Lowe, S. W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593–602 (1997). 40. Wei, W., Hemmer, R. M. & Sedivy, J. M. Role of p14ARF in replicative and induced senescence of human fibroblasts. Mol. Cell. Biol. 21, 6748–6757 (2001). 41. Wasilenko, W. J. & Marchok, A. C. Malic enzyme and malate dehydrogenase activities in rat tracheal epithelial cells during the progression of neoplasia. Cancer Lett. 28, 35–42 (1985). 42. Sauer, L. A., Dauchy, R. T.,Nagel, W. O.&Morris, H. P. Mitochondrial malic enzymes. Mitochondrial NAD(P)1-dependent malic enzyme activity and malate-dependent pyruvate formation are progression-linked in Morris hepatomas. J. Biol. Chem. 255, 3844–3848 (1980). 43. Nagel, W. O., Dauchy, R. T. & Sauer, L. A. Mitochondrial malic enzymes. An association between NAD(P)1-dependent malic enzyme and cell renewal in Sprague-Dawley rat tissues. J. Biol. Chem. 255, 3849–3854 (1980). 44. Braig, M. et al. Oncogene-induced senescence as an initial barrier in lymphoma development. Nature 436, 660–665 (2005). 45. Li, T. et al. Tumor suppression in the absence of p53-mediated cell-cycle arrest, apoptosis, and senescence. Cell 149, 1269–1283 (2012). 46. Brummelkamp, T. R., Bernards, R. & Agami, R. A system for stable expression of short interfering RNAs in mammalian cells. Science 296, 550–553 (2002). 47. Ventura, A. et al. Cre-lox-regulated conditionalRNAinterference fromtransgenes. Proc. Natl Acad. Sci. USA 101, 10380–10385 (2004). 48. Godar, S. et al. Growth-inhibitory and tumor-suppressive functions of p53 depend on its repression of CD44 expression. Cell 134, 62–73 (2008). 49. Jiang, P., Du, W., Heese, K. & Wu, M. The Bad guy cooperates with good cop p53: Bad is transcriptionally up-regulated by p53 and forms a Bad/p53 complex at the mitochondria to induce apoptosis. Mol. Cell. Biol. 26, 9071–9082 (2006). 50. Guay, C., Madiraju, S. R., Aumais, A., Joly, E. & Prentki, M. A role for ATP-citrate lyase, malic enzyme, and pyruvate/citrate cycling in glucose-induced insulin secretion. J. Biol. Chem. 282, 35657–35665 (2007). 51. Millard, P., Letisse, F., Sokol, S. & Portais, J. C. IsoCor: correcting MS data in isotope labeling experiments. Bioinformatics 28, 1294–1296 (2012). 52. Cossarizza, A. et al. Simultaneous analysis of reactive oxygen species and reduced glutathione content in living cells by polychromatic flow cytometry. Nature Protocols 4, 1790–1797 (2009). 53. Zhang, J. et al. AFAP-110 is overexpressed in prostate cancer and contributes to tumorigenic growth by regulating focal contacts. J. Clin. Invest. 117, 2962–2973 (2007). 54. Casares N, Pequignot MO, Tesniere A, Ghiringhelli F, Roux S, Chaput N et al. Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J Exp Med 2005; 202: 1691–1701. 55. Obeid M, Tesniere A, Ghiringhelli F, Fimia GM, Apetoh L, Perfettini JL et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med 2007; 13: 54–61. 56. Thompson CB. Apoptosis in the pathogenesis and treatment of disease.Science 1995; 267: 1456–1462. 57. Garg AD, Krysko DV, Verfaillie T, Kaczmarek A, Ferreira GB, Marysael T et al. A novel pathway combining calreticulin exposure and ATP secretion in immunogenic cancer cell death. EMBO J 2012; 31: 1062–1079. 58. Tanimoto T, Hori A, Kami M. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010; 363: 1967–1968 1966; author reply. 59. Galluzzi L, Vitale I, Abrams JM, Alnemri ES, Baehrecke EH, Blagosklonny MVet al. Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ 2012 19: 107–120. 60. Brenner C, Kroemer G. Apoptosis. Mitochondria–the death signal integrators.Science 2000; 289: 1150–1151. 61. Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol2007; 35: 495–516. 62. Krysko DV, Kaczmarek A, Krysko O, Heyndrickx L, Woznicki J, Bogaert P et al. TLR-2 and TLR-9 are sensors of apoptosis in a mouse model of doxorubicin-induced acute inflammation. Cell Death Differ 2011; 18: 1316–1325. 63. Panaretakis T, Kepp O, Brockmeier U, Tesniere A, Bjorklund AC, Chapman DCet al. Mechanisms of pre-apoptotic calreticulin exposure in immunogenic cell death. EMBO J 2009; 28: 578–590. 64. Merritt RE, Mahtabifard A, Yamada RE, Crystal RG, Korst RJ. Cisplatin augments cytotoxic T-lymphocyte-mediated antitumor immunity in poorly immunogenic murine lung cancer. J Thorac Cardiovasc Surg 2003; 126: 1609–1617. 65. Obeid M, Panaretakis T, Joza N, Tufi R, Tesniere A, van Endert P et al. Calreticulin exposure is required for the immunogenicity of gamma-irradiation and UVC light-induced apoptosis. Cell Death Differ 2007. 66. Suzuki Y, Mimura K, Yoshimoto Y, Watanabe M, Ohkubo Y, Izawa S et al. Immunogenic tumor cell death induced by chemoradiotherapy in patients with esophageal squamous cell carcinoma. Cancer Res 2012; 72: 3967–3976. 67. Rubner Y, Wunderlich R, Ruhle PF, Kulzer L, Werthmoller N, Frey B et al. How does ionizing irradiation contribute to the induction of anti-tumor immunity?Front Oncol 2012. 68. Dudek AM, Garg AD, Krysko DV, De Ruysscher D, Agostinis P. Inducers of immunogenic cancer cell death. Cytokine Growth Factor Rev 2013. 69. Panaretakis T, Joza N, Modjtahedi N, Tesniere A, Vitale I, Durchschlag M et al. The co-translocation of ERp57 and calreticulin determines the immunogenicity of cell death. Cell Death Differ 2008; 15: 1499–1509. 70. Apetoh L, Ghiringhelli F, Tesniere A, Obeid M, Ortiz C, Criollo A et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med 2007; 13: 1050–1059. 71. Schiavoni G, Sistigu A, Valentini M, Mattei F, Sestili P, Spadaro F et al. Cyclophosphamide synergizes with type I interferons through systemic dendritic cell reactivation and induction of immunogenic tumor apoptosis.Cancer Res 2011; 71: 768–778. 72. Chen J, Xie J, Jiang Z, Wang B, Wang Y, Hu X. Shikonin and its analogs inhibit cancer cell glycolysis by targeting tumor pyruvate kinase-M2.Oncogene 2011; 30: 4297–4306. 73. Yang H, Zhou P, Huang H, Chen D, Ma N, Cui QC et al. Shikonin exerts antitumor activity via proteasome inhibition and cell death induction in vitroand in vivo. Int J Cancer 2009; 124: 2450–2459. 74. Garrido G, Rabasa A, Sanchez B, Lopez MV, Blanco R, Lopez A et al. Induction of immunogenic apoptosis by blockade of epidermal growth factor receptor activation with a specific antibody. J Immunol 2011; 187: 4954–4966. 75. Menger L, Vacchelli E, Adjemian S, Martins I, Ma Y, Shen S et al. Cardiac glycosides exert anticancer effects by inducing immunogenic cell death. Sci Transl Med 2012; 4: 143ra199. 76. Sonnemann J, Gressmann S, Becker S, Wittig S, Schmudde M, Beck JF. The histone deacetylase inhibitor vorinostat induces calreticulin exposure in childhood brain tumour cells in vitro. Cancer Chemother Pharmacol 2010;66: 611–616. 77. Han W, Li L, Qiu S, Lu Q, Pan Q, Gu Y et al. Shikonin circumvents cancer drug resistance by induction of a necroptotic death. Mol Cancer Ther 2007;6: 1641–1649. 78. Galluzzi L, Kepp O, Kroemer G. Enlightening the impact of immunogenic cell death in photodynamic cancer therapy. EMBO J 2012; 31: 1055–1057. 79. Scaffidi P, Misteli T, Bianchi ME. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 2002; 418: 191–195. 80. Zhang L, Wang A. Virus-induced ER stress and the unfolded protein response. Front Plant Sci 2012; 3: 293. 81. Schwarz KB. Oxidative stress during viral infection: a review. Free Radic Biol Med 1996; 21: 641–649. 82. Garg AD, Krysko DV, Vandenabeele P, Agostinis P. Hypericin-based photodynamic therapy induces surface exposure of damage-associated molecular patterns like HSP70 and calreticulin. Cancer Immunol Immunother2012; 61: 215–221. 83. Martin SJ, Reutelingsperger CP, McGahon AJ, Rader JA, van Schie RC, LaFace DM et al. Early redistribution of plasma membrane phosphatidylserine is a general feature of apoptosis regardless of the initiating stimulus: inhibition by overexpression of Bcl-2 and Abl. J Exp Med 1995; 182: 1545–1556. 84. Martins I, Kepp O, Schlemmer F, Adjemian S, Tailler M, Shen S et al. Restoration of the immunogenicity of cisplatin-induced cancer cell death by endoplasmic reticulum stress. Oncogene 2011; 30: 1147–1158. 85. Garg AD, Nowis D, Golab J, Vandenabeele P, Krysko DV, Agostinis P. Immunogenic cell death, DAMPs and anticancer therapeutics: an emerging amalgamation. Biochim Biophys Acta 2010; 1805: 53–71. 86. Kazama H, Ricci JE, Herndon JM, Hoppe G, Green DR, Ferguson TA. Induction of immunological tolerance by apoptotic cells requires caspase-dependent oxidation of high-mobility group box-1 protein. Immunity 2008; 29: 21–32. 87. Apetoh L, Ghiringhelli F, Tesniere A, Criollo A, Ortiz C, Lidereau R et al. The interaction between HMGB1 and TLR4 dictates the outcome of anticancer chemotherapy and radiotherapy. Immunol Rev 2007; 220: 47–59. 88. Yang H, Hreggvidsdottir HS, Palmblad K, Wang H, Ochani M, Li J et al. A critical cysteine is required for HMGB1 binding to Toll-like receptor 4 and activation of macrophage cytokine release. Proc Natl Acad Sci USA 2010;107: 11942–11947. 89. Guo ZS, Naik A, O''Malley ME, Popovic P, Demarco R, Hu Y et al. The enhanced tumor selectivity of an oncolytic vaccinia lacking the host range and antiapoptosis genes SPI-1 and SPI-2. Cancer Res 2005; 65: 9991–9998. 90. Diaconu I, Cerullo V, Hirvinen ML, Escutenaire S, Ugolini M, Pesonen SK et al. Immune response is an important aspect of the antitumor effect produced by a CD40L-encoding oncolytic adenovirus. Cancer Res 2012; 72: 2327–2338. 91. Elliott MR, Chekeni FB, Trampont PC, Lazarowski ER, Kadl A, Walk SF et al. Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. Nature 2009; 461: 282–286. 92. Martins I, Tesniere A, Kepp O, Michaud M, Schlemmer F, Senovilla L et al. Chemotherapy induces ATP release from tumor cells. Cell Cycle 2009; 8: 3723–3728. 93. Michaud M, Martins I, Sukkurwala AQ, Adjemian S, Ma Y, Pellegatti P et al. Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science 2011; 334: 1573–1577. 94. Ohshima Y, Tsukimoto M, Takenouchi T, Harada H, Suzuki A, Sato M et al. Gamma-irradiation induces P2X(7) receptor-dependent ATP release from B16 melanoma cells. Biochim Biophys Acta 2010; 1800: 40–46. 95. Petrovski G, Ayna G, Majai G, Hodrea J, Benko S, Madi A et al. Phagocytosis of cells dying through autophagy induces inflammasome activation and IL-1beta release in human macrophages. Autophagy 2011; 7: 321–330. 96. Chang CW, Li HC, Hsu CF, Chang CY, Lo SY. Increased ATP generation in the host cell is required for efficient vaccinia virus production. J Biomed Sci2009; 16: 80. 97. Maiuri MC, Zalckvar E, Kimchi A, Kroemer G. Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol 2007; 8: 741–752. 98. Amaravadi RK, Thompson CB. The roles of therapy-induced autophagy and necrosis in cancer treatment. Clin Cancer Res 2007; 13: 7271–7279. 99. Klionsky DJ, Emr SD. Autophagy as a regulated pathway of cellular degradation. Science 2000; 290: 1717–1721. 100. Eisenberg-Lerner A, Bialik S, Simon HU, Kimchi A. Life and death partners: apoptosis, autophagy and the cross-talk between them. Cell Death Differ2009; 16: 966–975. 101. Kroemer G, Levine B. Autophagic cell death: the story of a misnomer. Nat Rev Mol Cell Biol 2008; 9: 1004–1010. 102. Qu X, Zou Z, Sun Q, Luby-Phelps K, Cheng P, Hogan RN et al. Autophagy gene-dependent clearance of apoptotic cells during embryonic development.Cell 2007; 128: 931–946. 103. Martins I, Michaud M, Sukkurwala AQ, Adjemian S, Ma Y, Shen S et al. Premortem autophagy determines the immunogenicity of chemotherapy-induced cancer cell death. Autophagy 2012; 8: 413–415. 104. Townsend KN, Hughson LR, Schlie K, Poon VI, Westerback A, Lum JJ. Autophagy inhibition in cancer therapy: metabolic considerations for antitumor immunity. Immunol Rev 2012; 249: 176–194. 105. Amaravadi RK, Yu D, Lum JJ, Bui T, Christophorou MA, Evan GI et al. Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J Clin Invest 2007; 117: 326–336. 106. Yang ZJ, Chee CE, Huang S, Sinicrope FA. The role of autophagy in cancer: therapeutic implications. Mol Cancer Ther 2011; 10: 1533–1541. 107. Vandenabeele P, Declercq W, Van Herreweghe F, Vanden Berghe T. The role of the kinases RIP1 and RIP3 in TNF-induced necrosis. Sci Signal 2010; 3: re4. 108. Wyllie AH, Kerr JF, Currie AR. Cell death: the significance of apoptosis. Int Rev Cytol 1980; 68: 251–306. 109. Van Herreweghe F, Festjens N, Declercq W, Vandenabeele P. Tumor necrosis factor-mediated cell death: to break or to burst, that''s the question. Cell Mol Life Sci 2010; 67: 1567–1579. 110. Zhang DW, Shao J, Lin J, Zhang N, Lu BJ, Lin SC et al. RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science 2009; 325: 332–336. 111. Holler N, Zaru R, Micheau O, Thome M, Attinger A, Valitutti S et al. Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat Immunol 2000; 1: 489–495. 112. Kamata H, Honda S, Maeda S, Chang L, Hirata H, Karin M. Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell 2005; 120: 649–661. 113. Skulachev VP. Bioenergetic aspects of apoptosis, necrosis and mitoptosis.Apoptosis 2006; 11: 473–485. 114. Todaro M, Alea MP, Di Stefano AB, Cammareri P, Vermeulen L, Iovino F et al. Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4. Cell Stem Cell 2007; 1: 389–402. 115. Madjd Z, Mehrjerdi AZ, Sharifi AM, Molanaei S, Shahzadi SZ, Asadi-Lari M. CD44+ cancer cells express higher levels of the anti-apoptotic protein Bcl-2 in breast tumours. Cancer Immun 2009; 9: 4. 116. Bergsbaken T, Fink SL, Cookson BT. Pyroptosis: host cell death and inflammation. Nat Rev Microbiol 2009; 7: 99–109. 117. Colunga AG, Laing JM, Aurelian L. The HSV-2 mutant DeltaPK induces melanoma oncolysis through nonredundant death programs and associated with autophagy and pyroptosis proteins. Gene Ther 2010; 17: 315–327. 118. Galluzzi L, Brenner C, Morselli E, Touat Z, Kroemer G. Viral control of mitochondrial apoptosis. PLoS Pathogen 2008; 4: e1000018. 119. Moussavi M, Fazli L, Tearle H, Guo Y, Cox M, Bell J et al. Oncolysis of prostate cancers induced by vesicular stomatitis virus in PTEN knockout mice. Cancer Res 2010; 70: 1367–1376. 120. Jablonska J, Leschner S, Westphal K, Lienenklaus S, Weiss S. Neutrophils responsive to endogenous IFN-beta regulate tumor angiogenesis and growth in a mouse tumor model. J Clin Invest 2010; 120: 1151–1164. 121. Kanai R, Wakimoto H, Martuza RL, Rabkin SD. A novel oncolytic herpes simplex virus that synergizes with phosphoinositide 3-kinase/Akt pathway inhibitors to target glioblastoma stem cells. Clin Cancer Res 2011; 17: 3686–3696.
摘要: 
蘋果酸酶 (Malic Enzyme; ME) 具有三種異構型,其中粒線體蘋果酸酶 (Mitochondrial NAD(P)+-dependent malic enzyme;ME2) 作用於快速增生的組織、小腸黏膜細胞、脾臟、胸腺與腫瘤細胞;ME2 催化受質蘋果酸 (Malate) 生成產物丙酮酸 (Pyruvate),同時伴隨產生NADH。NADH 在粒線體內膜電子傳遞鏈經氧化磷酸作用直接產生 ATP 提供細胞能量,過程中有機率會產生 O2-,經由 Superoxide Dismutase (SOD) 催化生成 H2O2,最後利用金屬離子協助形成OH-,對細胞進行氧化作用造成傷害,進而活化下游的蛋白,發生程式性的計畫死亡 (Apoptosis)。ME2 催化反應伴隨產生的 NADH 作為能量代謝分子 ATP 的主要來源,同時在對抗細胞內活性氧傷害可能也扮演極重要的角色,協助 NADPH 產生並促使 Glutathione (GSH) 保持於還原態,有效減低 ROS 的傷害。而在抗癌機制的研究中,除了促使癌細胞凋亡外,還要抑制增生途徑,我同時進行的研究方向還有針對粒線體蘋果酸酶 (Malic enzyme 2, ME2)對於細胞增生機制與粒線體蘋果酸酶活性具有相關性,粒線體蘋果酸酶是細胞裡另外一個獲取能量的途徑,許多腫瘤細胞可以利用穀胺酸 (glutamine) 來取代葡萄糖成為主要的能量來源,蘋果酸酶催化作用即與穀胺酸的代謝有關,稱之為「Glutaminolysis」;代謝過程中,α-ketoglutarate 轉化成蘋果酸 (malate) 係由三羧酸循環 (citric acid cycle) 中的酵素催化。正常細胞內的蘋果酸在三羧酸循環中由蘋果酸去氫酶 (malate dehydrogenase) 催化為oxaloacetate;但在 Glutaminolysis 過程中,蘋果酸則由蘋果酸酶催化形成丙酮酸(pyruvate)。在檸檬酸循環中的蘋果酸 (Malate) 會藉由 ME2 的催化作用轉變成丙酮酸和二氧化碳伴隨著 NADH 的產生,使細胞獲得能量並促使細胞增生。除此之外,癌症細胞大部分從表皮生成,所以表皮生長因子 EGF 在癌症中相較其他生長因子最具普遍性也最具研究潛力,而且也發現 ATP 能促使 EGFR 的活性增加,推測 EGF 和 ME2有相互影響的可能性。接著探討 ME2 於 H1299 肺癌細胞 (非小細胞肺癌) 中是否相較於一般肺細胞過量表現,及過度表現ME2後是否能活化 AKT/PI3K signaling pathway與ERK/MAPK signaling pathway來促使細胞增生;之後也可以藉由Repamycin (mTOR 抑制劑) 來探討 EGF 和 ME2 的活化路徑,進一步研究抑制 H1299 肺癌細胞株增生的途徑。

Malic enzyme (Malic Enzyme; ME) has three isoforms, which mitochondrial malic enzyme (Mitochondrial NAD (P) +-dependent malic enzyme; ME2) acting on the rapid proliferation of tissue, intestinal mucosa, spleen, thymus and tumor cells; ME2 catalytic substrates malate (Malate) generate pyruvate (Pyruvate), accompanied produce NADH. NADH in the mitochondrial membrane electron transport chain via oxidative phosphorylation to produce ATP provides direct role in cellular energy, the process will have a chance to produce O2-, via Superoxide Dismutase (SOD) catalyzes the formation of H2O2. Finally, to assist the formation of metal ions OH-, on the cell undergoes oxidation damage, thus activating downstream proteins, the occurrence of procedural plans death (Apoptosis). ME2 catalytic reaction accompanied by NADH generated energy metabolism as a major source of ATP molecules, while in the fight against ROS damage may also play a very important role in helping to generate and promote NADPH Glutathione (GSH) maintained at reduced state, effectively reduce the ROS injury. In the anticancer mechanism, in addition to promote apoptosis in cancer cells, but also inhibit the proliferation of channels, I also conducted research there for mitochondrial malic enzyme (Malic enzyme 2, ME2) mechanism for cell proliferation mitochondrial malic enzyme activity is correlated mitochondrial malic enzyme is a cell in another to obtain energy pathways, many tumor cells can use glutamine (glutamine) to replace glucose as a major energy source, malic enzyme ie the catalytic glutamate metabolism, called "Glutaminolysis". Metabolic process, α-ketoglutarate converted to malate system by the Krebs cycle (citric acid cycle) in enzyme catalysis. Normal intracellular malic acid in the Krebs cycle by malate dehydrogenase (malate dehydrogenase) catalysis of oxaloacetate; But in Glutaminolysis process, malic acid from malic enzyme catalyzed the formation of pyruvic acid (pyruvate). In the citric acid cycle malic acid (Malate) will be converted into the catalysis by ME2 pyruvate and NADH accompanied by the generation of carbon dioxide, the cells get energy and to promote cell proliferation. In addition, the majority of cancer cells generated from the epidermis, so epidermal growth factor EGF in cancer compared to other growth factors most universal and most research potential, but also found that ATP can induce increased activity of EGFR, suggesting that EGF and ME2 has the possibility of mutual influence. Then explore the ME2 in H1299 lung cancer cells (non-small cell lung cancer) than in normal lung cells whether overexpression, and overexpression of whether ME2 AKT/PI3K signaling pathway can be activated with the ERK / MAPK signaling pathway to induce cell proliferation; even after can be contacted by Repamycin (mTOR inhibitor) to investigate the activation of EGF and ME2 path, further research H1299 lung cancer cell proliferation inhibition ways.
URI: http://hdl.handle.net/11455/20227
其他識別: U0005-2308201315280100
Appears in Collections:生命科學系所

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