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系統識別號 U0026-2607201113092800
論文名稱(中文) 銅輸送蛋白hCtr1在cisplatin化學治療的角色探討
論文名稱(英文) Role of Human Copper Transporter 1 (hCtr1) in Cisplatin Chemotherapy
校院名稱 成功大學
系所名稱(中) 臨床醫學研究所
系所名稱(英) Institute of Clinical Medicine
學年度 99
學期 2
出版年 100
研究生(中文) 陳海雯
研究生(英文) Helen H.W. Chen
學號 s9891103
學位類別 博士
語文別 英文
論文頁數 95頁
口試委員 指導教授-蘇五洲
指導教授-劉校生
召集委員-林秋烽
口試委員-施能耀
口試委員-林進清
中文關鍵字 銅輸送蛋白hCtr1  順鉑  抗藥性  麩胱甘肽合成酵素  轉錄因子Sp1  銅平衡狀態  治療預後 
英文關鍵字 human copper transporter 1 (hCtr1)  cisplatin  drug resistance  glutamate-cysteine ligase catalytic (GCLC) subunit  transcription factor Sp1  copper homeostasis  prognosis 
學科別分類
中文摘要 鉑金類化學藥物順鉑(cisplatin, CDDP)是現今治療許多癌症的最主要抗腫瘤藥物,然而癌細胞產生抗藥性與腎臟毒性是其化學治療失效的重要原因與治療限制。抗癌藥物進入細胞的能力影響到細胞內的藥物囤積量,亦是抗藥性的重要機轉之一。過去不清楚細胞有無CDDP的輸入蛋白,最近才有研究顯示生物體內輸送銅離子的銅輸送蛋白(human copper transport 1, hCtr1)也可能參與CDDP的運輸。
我研究麩胱甘肽(glutathione, GSH)過度表達的細胞株對CDDP藥物敏感性的影響,將控制生物體生合成GSH的酵素glutamyl cysteine synthetase catalytic subunit (GCLC) cDNA質體外送入細胞,發現GSH含量高的細胞株對CDDP的敏感性大幅提高,主要原因是因為細胞內的銅輸送蛋白hCtr1增加之故。若降低這些細胞內GSH的含量,則hCtr1的表達量會降低而使CDDP的敏感性逆轉。雖然這些高表達hCtr1細胞株的銅離子攝入量增加,細胞卻表現出銅缺乏的許多生化特性,顯示在細胞內GSH可能會與銅結合成螯合物而影響細胞內銅的代謝反應,這是過去不曾被發表的調控GSH影響化學藥物抗藥性的新機制。
進一步研究調控hCtr1的作用機制,我發現hCtr1對維持生物體內的銅平衡狀態扮演非常重要的角色,hCtr1 mRNA在銅減少的情況下其產量會增加,反之在銅充裕的情況下hCtr1 mRNA產量會減少。將hCtr1 cDNA轉送進入活體細胞中,hCtr1蛋白會過量表達,同時其內源性hCtr1 mRNA的產量則會被抑制。若將去除蛋白質N端的hCtr1過量表達,則其內源性hCtr1 mRNA的產量將不受影響,顯示唯有增加有功能的hCtr1,其細胞內的銅含量才會增加,才會同時抑制其內源性hCtr1 mRNA的產量,所以hCtr1蛋白表現是受到轉錄層面的調控,且有自己調控自己的能力。我還發現hCtr1基因的啟動子區域含有三個轉錄因子Sp1的結合處,此三處均受銅離子的影響而調控hCtr1的表現,且調控Sp1會影響hCtr1蛋白的表達,所以Sp1是哺乳類動物中調控hCtr1的重要因子,Sp1也影響細胞內銅離子微妙的平衡狀態。進一步研究證明Sp1的鋅指結合區(zinc-finger domain)是感應銅濃度變化之處,會隨著銅濃度的起伏變化而調控hCtr1。此發現證實哺乳類細胞的銅平衡狀態,是受到轉錄層面hCtr1蛋白的調控,且被轉錄因子Sp1所調節。
目前尚無hCtr1在臨床上意義的相關研究,我發現在接受第一線含CDDP藥物化學治療的第三期非小細胞肺癌病人中,hCtr1在腫瘤的表達不但可預測CDDP藥物化學治療的療效,也是重要的預後因子,高表達hCtr1的腫瘤有較好的化學治療療效與較佳的無疾病惡化與整體存活率,而銅輸出蛋白ATP7A和ATP7B則對預後無影響。在另一群手術後局部復發的子宮頸癌病人族群,我也發現hCtr1在腫瘤的表達是接受救援性放射治療合併CDDP化學治療的重要預後因子。
這些對於鉑金類化學藥物抗藥性的傳統觀念突破,以及銅輸送蛋白hCtr1對CDDP化學治療在臨床上的預測療效與治療預後所扮演的重要角色,對未來篩選合適病人接受CDDP化學治療,或是藉由調控細胞中的銅平衡狀態以促進CDDP化學治療效果,將可能造成重要影響。
英文摘要 Cisplatin (CDDP) chemotherapy has been the mainstay for the treatment of a broad spectrum of solid tumors. Drug resistance and nephrotoxicity are the major limitations on the use of this important antineoplastic agent. One mechanism associated with resistance to cisplatin is reduced intracellular accumulation owing to impaired drug intake. Mechanisms for transporting cisplatin were not known until recent demonstrations that human copper transporter 1 (hCtr1), the major copper influx transporter, is also involved in the transport of these drugs.
I studied glutathione (GSH)-overexpressing cell lines, established by stably transfecting the GSH rate-limiting enzyme glutamate-cysteine ligase catalytic subunit (GCLC) cDNA plasmid. I found that overexpression of GSH confer sensitization to CDDP through up-regulation of human copper transporter 1 (hCtr1). Depleting GSH levels in these transfected cells reverses CDDP sensitivity with concomitant reduction of hCtr1 expression. Although rates of copper transport were also up-regulated in the transfected cells, these cells exhibited biochemical signature of copper deficiency, suggesting that GSH functions as an intracellular copper-chelator and that overexpression of GSH can alter copper metabolism. Our results reveal a new role of GSH in the regulation of CDDP sensitivity.
To further investigate the regulating mechanism of hCtr1, I found that hCtr1 plays an important role in the maintenance of copper homeostasis. Expression of hCtr1 mRNA is up-regulated under copper-depleted conditions and down-regulated under copper-repleted conditions. Overexpression of full-length hCtr1 reduces endogenous hCtr1 mRNA levels, whereas overexpression of N terminus-depleted hCtr1 does not change endogenous hCtr1 mRNA levels. This suggests that increasing functional hCtr1 transporter, which leads to increased intracellular copper content, down-regulates the endogenous hCtr1 mRNA. I also found that three Sp1 binding sites in the hCtr1 promoter region are involved in the basal and copper concentration-dependent regulation of hCtr1 expression. I further demonstrated that the zinc-finger domain of Sp1 functions as a sensor of copper that regulates hCtr1 up and down in response to variations in copper concentration.
Using patients’ clinical data and tumor samples at the National Cheng Kung University Hospital, I have consolidated the link between hCtr1 protein expressions in cancer patients receiving CDDP chemotherapy. I investigated hCtr1 expression in advanced non-small cell lung cancer (NSCLC) and cervical cancer, and assessed if tumoral hCtr1 protein levels were predictive of response to CDDP-containing chemotherapy. I found that hCtr1 is not only an independent predictor for good responses of CDDP-containing chemotherapy, but also a prognostic factor for progression-free and overall survival in stage III NSCLC patients receiving first-line platinum-based doublet chemotherapy. I also found that hCtr1 is of prognostic value in locally recurrent cervical cancer receiving salvage CDDP chemotherapy and radiation therapy.
These findings shall provide a new paradigm for future research in gaining molecular insights into the complex regulatory circuitry in mammalian Cu homeostasis. It may also have important clinical implications in that modulation of the intracellular copper pool for enhancing tumor-specific uptake of CDDP in cancer chemotherapy.
論文目次 中文摘要 I
ABSTRACT IV
誌謝 VII
目錄 IX
表目錄 XI
圖目錄 XII
BACKGROUND 1
1. CISPLATIN CHEMOTHERAPY AND DRUG RESISTANCE 1
2. IDENTIFICATION OF COPPER TRANSPORTER HCTR1 AS CDDP TRANSPORTER 2
3. REGULATION OF COPPER HOMEOSTASIS BY HCTR1 4
4. ROLE OF GLUTATHIONE (GSH) IN HCTR1-MEDIATED CDDP TRANSPORT 6
5. CLINICAL IMPLICATIONS OF HCTR1 IN CDDP CHEMOTHERAPY 8
SPECIFIC AIMS 9
MATERIALS AND METHODS 11
CELL CULTURE AND TRANSFECTION WITH GCLC-INDUCIBLE RECOMBINANT ADENOVIRUS. 11
DETERMINATION OF DRUG SENSITIVITY. 11
MEASUREMENTS OF COPPER AND CDDP UPTAKE. 12
PLASMID DNA 12
CELL CULTURE AND TREATMENTS WITH METAL IONS AND METAL CHELATORS 14
MEASUREMENTS OF CYTOCHROME C OXIDASE AND SUPEROXIDE DISMUTASE 1 ACTIVITIES AND CERULOPLASMIN ENZYME PROFILE. 15
RNASE PROTECTION ASSAY. 15
LUCIFERASE ASSAY. 16
WESTERN BLOT ANALYSIS. 17
ELECTROPHORETIC MOBILITY SHIFT ASSAYS. 17
SIRNA TRANSFECTION. 18
PATIENTS AND TREATMENT. 18
1) RECURRENT CERVICAL CARCINOMA 18
2) STAGE III NON-SMALL CELL LUNG CANCER (NSCLC) 20
IMMUNOHISTOCHEMISTRY 21
STATISTICAL ANALYSIS 22
RESULTS 24
I. ELEVATED GSH LEVELS CONFER CELLULAR SENSITIZATION TO CDDP TOXICITY BY UP-REGULATION OF HCTR1. 24
I.1. Elevated Expression of GSH in GCLC-Transfected Cells Sensitizes Cells to CDDP But Not to Copper. 24
I.2. GCLC-Transfected Cells Showed Increased Transport Activities of CDDP and Cu. 25
I.3. Down Regulation of the Overexpressed hCtr1 mRNA in the GCLC-transfected Cells by siRNA Resulted in Enhanced Resistance to CDDP. 27
I.4. Elevated GSH Levels Reduces Bioavailable Pool of Cu That Upregulates hCtr1 Expression. 27
I.5. Reduction of GSH Levels in the GCLC-Transfected Cells Reverses CDDP Sensitivity and hCtr1 Expression. 29
II. TRANSCRIPTION FACTOR SP1 PLAYS AN IMPORTANT ROLE IN THE REGULATION OF COPPER HOMEOSTASIS IN MAMMALIAN CELLS. 32
II.1. Steady-State hCtr1 mRNA Levels Are Regulated by Copper Concentration. 32
II.2. Steady-State Levels of hCtr1 mRNA Are Self-Regulated. 33
II.3. Transcriptional Regulation of hCtr1 Expression by Copper. 35
II.4. Sp1 Functions as a Positive Regulator for hCtr1 Expression at Normal Copper Concentration. 38
II.5. ZFs in Sp1 Function as Sensors of Copper Stress Conditions. 39
III. CLINICAL RELEVANCE OF HCTR1 IN CDDP CHEMOTHERAPY. 41
III.1. Prognostic value of hCt1 in recurrent cervical carcinoma patients receiving salvage radiation therapy and CDDP-based chemotherapy. 41
Expression of hCtr1 immunostaining 41
Progression-free survival (PFS) and overall survival (OS) and hCtr1 immunostaining 42
III.2. Predictive and prognostic values of hCt1 in NSCLC patients receiving first-line platinum-based doublet chemotherapy. 43
Predictive impact of hCtr1, ATP7A and ATP7B immunostainings on measurable tumor response 43
Impact of hCtr1, ATP7A and ATP7B immunostainings on survival 44
DISCUSSION AND CONCLUSION 46
REFERENCES 55
TABLES 67
FIGURES 72
LIST OF DISSERTATION-RELATED PUBLICATIONS 89
CURRICULUM VITAE (C.V.) 91
參考文獻 (1) Hussain SA, Ma YT, Cullen MH: Management of metastatic germ cell tumors. Expert Rev Anticancer Ther 2008; 8(5):771-784.
(2) Omura GA: Progress in gynecologic cancer research: the Gynecologic Oncology Group experience. Semin Oncol 2008; 35(5):507-521.
(3) Gallagher DJ, Milowsky MI, Bajorin DF: Advanced bladder cancer: status of first-line chemotherapy and the search for active agents in the second-line setting. Cancer 2008; 113(6):1284-1293.
(4) Yang ES, Murphy BM, Chung CH, Netterville JL, Burkey BB, Gilbert J, Yarbrough WG, Sinard R, Cmelak AJ: Evolution of clinical trials in head and neck cancer. Crit Rev Oncol Hematol 2009; 71(1):29-42.
(5) Lustberg MB, Edelman MJ: Optimal duration of chemotherapy in advanced non-small cell lung cancer. Curr Treat Options Oncol 2007; 8(1):38-46.
(6) Fischer B, Arcaro A: Current status of clinical trials for small cell lung cancer. Rev Recent Clin Trials 2008; 3(1):40-61.
(7) Cen P, Ajani JA: Medical treatment for advanced gastroesophageal adenocarcinoma. Curr Opin Gastroenterol 2007; 23(6):631-635.
(8) Oh WK, Tay MH, Huang J: Is there a role for platinum chemotherapy in the treatment of patients with hormone-refractory prostate cancer? Cancer 2007; 109(3):477-486.
(9) Saif MW, Kim R: Role of platinum agents in the management of advanced pancreatic cancer. Expert Opin Pharmacother 2007; 8(16):2719-2727.
(10) Carrick S, Ghersi D, Wilcken N, Simes J: Platinum containing regimens for metastatic breast cancer. Cochrane Database Syst Rev 2004;(2):CD003374.
(11) Giaccone G: Clinical perspectives on platinum resistance. Drugs 2000; 59 Suppl 4:9-17.
(12) Daugaard G, Abildgaard U: Cisplatin nephrotoxicity. A review. Cancer Chemother Pharmacol 1989; 25(1):1-9.
(13) Lokich J, Anderson N: Carboplatin versus cisplatin in solid tumors: an analysis of the literature. Ann Oncol 1998; 9(1):13-21.
(14) Raymond E, Faivre S, Chaney S, Woynarowski J, Cvitkovic E: Cellular and molecular pharmacology of oxaliplatin. Mol Cancer Ther 2002; 1(3):227-235.
(15) Siddik ZH: Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene 2003; 22(47):7265-7279.
(16) Wang D, Lippard SJ: Cellular processing of platinum anticancer drugs. Nat Rev Drug Discov 2005; 4(4):307-320.
(17) Song IS, Savaraj N, Siddik ZH, Liu P, Wei Y, Wu CJ, Kuo MT: Role of human copper transporter Ctr1 in the transport of platinum-based antitumor agents in cisplatin-sensitive and cisplatin-resistant cells. Mol Cancer Ther 2004; 3(12):1543-1549.
(18) Johnson SW, Laub PB, Beesley JS, Ozols RF, Hamilton TC: Increased platinum-DNA damage tolerance is associated with cisplatin resistance and cross-resistance to various chemotherapeutic agents in unrelated human ovarian cancer cell lines. Cancer Res 1997; 57(5):850-856.
(19) Hall MD, Okabe M, Shen DW, Liang XJ, Gottesman MM: The role of cellular accumulation in determining sensitivity to platinum-based chemotherapy. Annu Rev Pharmacol Toxicol 2008; 48:495-535.
(20) Komatsu M, Sumizawa T, Mutoh M, Chen ZS, Terada K, Furukawa T, Yang XL, Gao H, Miura N, Sugiyama T, Akiyama S: Copper-transporting P-type adenosine triphosphatase (ATP7B) is associated with cisplatin resistance. Cancer Res 2000; 60(5):1312-1316.
(21) Miyashita H, Nitta Y, Mori S, Kanzaki A, Nakayama K, Terada K, Sugiyama T, Kawamura H, Sato A, Morikawa H, Motegi K, Takebayashi Y: Expression of copper-transporting P-type adenosine triphosphatase (ATP7B) as a chemoresistance marker in human oral squamous cell carcinoma treated with cisplatin. Oral Oncol 2003; 39(2):157-162.
(22) Kuo MT, Chen HH, Song IS, Savaraj N, Ishikawa T: The roles of copper transporters in cisplatin resistance. Cancer Metastasis Rev 2007; 26(1):71-83.
(23) Ishida S, Lee J, Thiele DJ, Herskowitz I: Uptake of the anticancer drug cisplatin mediated by the copper transporter Ctr1 in yeast and mammals. Proc Natl Acad Sci U S A 2002; 99(22):14298-14302.
(24) Jungmann J, Reins HA, Lee J, Romeo A, Hassett R, Kosman D, Jentsch S: MAC1, a nuclear regulatory protein related to Cu-dependent transcription factors is involved in Cu/Fe utilization and stress resistance in yeast. EMBO J 1993; 12(13):5051-5056.
(25) Lin X, Okuda T, Holzer A, Howell SB: The copper transporter CTR1 regulates cisplatin uptake in Saccharomyces cerevisiae. Mol Pharmacol 2002; 62(5):1154-1159.
(26) Kuo YM, Zhou B, Cosco D, Gitschier J: The copper transporter CTR1 provides an essential function in mammalian embryonic development. Proc Natl Acad Sci U S A 2001; 98(12):6836-6841.
(27) Lee J, Prohaska JR, Thiele DJ: Essential role for mammalian copper transporter Ctr1 in copper homeostasis and embryonic development. Proc Natl Acad Sci U S A 2001; 98(12):6842-6847.
(28) Nose Y, Rees EM, Thiele DJ: Structure of the Ctr1 copper trans'PORE'ter reveals novel architecture. Trends Biochem Sci 2006; 31(11):604-607.
(29) Puig S, Thiele DJ: Molecular mechanisms of copper uptake and distribution. Curr Opin Chem Biol 2002; 6(2):171-180.
(30) Harris ED: Basic and clinical aspects of copper. Crit Rev Clin Lab Sci 2003; 40(5):547-586.
(31) Sharp PA: Ctr1 and its role in body copper homeostasis. Int J Biochem Cell Biol 2003; 35(3):288-291.
(32) Shim H, Harris ZL: Genetic defects in copper metabolism. J Nutr 2003; 133(5 Suppl 1):1527S-1531S.
(33) Cai L, Li XK, Song Y, Cherian MG: Essentiality, toxicology and chelation therapy of zinc and copper. Curr Med Chem 2005; 12(23):2753-2763.
(34) Uriu-Adams JY, Keen CL: Copper, oxidative stress, and human health. Mol Aspects Med 2005; 26(4-5):268-298.
(35) Garrick MD, Dolan KG, Horbinski C, Ghio AJ, Higgins D, Porubcin M, Moore EG, Hainsworth LN, Umbreit JN, Conrad ME, Feng L, Lis A, Roth JA, Singleton S, Garrick LM: DMT1: a mammalian transporter for multiple metals. Biometals 2003; 16(1):41-54.
(36) Jensen LT, Posewitz MC, Srinivasan C, Winge DR: Mapping of the DNA binding domain of the copper-responsive transcription factor Mac1 from Saccharomyces cerevisiae. J Biol Chem 1998; 273(37):23805-23811.
(37) Jamison McDaniels CP, Jensen LT, Srinivasan C, Winge DR, Tullius TD: The yeast transcription factor Mac1 binds to DNA in a modular fashion. J Biol Chem 1999; 274(38):26962-26967.
(38) Jensen LT, Winge DR: Identification of a copper-induced intramolecular interaction in the transcription factor Mac1 from Saccharomyces cerevisiae. EMBO J 1998; 17(18):5400-5408.
(39) Rutherford JC, Bird AJ: Metal-responsive transcription factors that regulate iron, zinc, and copper homeostasis in eukaryotic cells. Eukaryot Cell 2004; 3(1):1-13.
(40) Winge DR: Copper-regulatory domain involved in gene expression. Prog Nucleic Acid Res Mol Biol 1998; 58:165-195.
(41) Yamaguchi-Iwai Y, Serpe M, Haile D, Yang W, Kosman DJ, Klausner RD, Dancis A: Homeostatic regulation of copper uptake in yeast via direct binding of MAC1 protein to upstream regulatory sequences of FRE1 and CTR1. J Biol Chem 1997; 272(28):17711-17718.
(42) Ooi CE, Rabinovich E, Dancis A, Bonifacino JS, Klausner RD: Copper-dependent degradation of the Saccharomyces cerevisiae plasma membrane copper transporter Ctr1p in the apparent absence of endocytosis. EMBO J 1996; 15(14):3515-3523.
(43) Yonkovich J, McKenndry R, Shi X, Zhu Z: Copper ion-sensing transcription factor Mac1p post-translationally controls the degradation of its target gene product Ctr1p. J Biol Chem 2002; 277(27):23981-23984.
(44) Selvaraj A, Balamurugan K, Yepiskoposyan H, Zhou H, Egli D, Georgiev O, Thiele DJ, Schaffner W: Metal-responsive transcription factor (MTF-1) handles both extremes, copper load and copper starvation, by activating different genes. Genes Dev 2005; 19(8):891-896.
(45) Zhou B, Gitschier J: hCTR1: a human gene for copper uptake identified by complementation in yeast. Proc Natl Acad Sci U S A 1997; 94(14):7481-7486.
(46) Petris MJ, Smith K, Lee J, Thiele DJ: Copper-stimulated endocytosis and degradation of the human copper transporter, hCtr1. J Biol Chem 2003; 278(11):9639-9646.
(47) Eisses JF, Chi Y, Kaplan JH: Stable plasma membrane levels of hCTR1 mediate cellular copper uptake. J Biol Chem 2005; 280(10):9635-9639.
(48) Godwin AK, Meister A, O'Dwyer PJ, Huang CS, Hamilton TC, Anderson ME: High resistance to cisplatin in human ovarian cancer cell lines is associated with marked increase of glutathione synthesis. Proc Natl Acad Sci U S A 1992; 89(7):3070-3074.
(49) Meijer C, Mulder NH, Timmer-Bosscha H, Sluiter WJ, Meersma GJ, de Vries EG: Relationship of cellular glutathione to the cytotoxicity and resistance of seven platinum compounds. Cancer Res 1992; 52(24):6885-6889.
(50) Schroder CP, Godwin AK, O'Dwyer PJ, Tew KD, Hamilton TC, Ozols RF: Glutathione and drug resistance. Cancer Invest 1996; 14(2):158-168.
(51) Mishima K, Baba A, Matsuo M, Itoh Y, Oishi R: Protective effect of cyclic AMP against cisplatin-induced nephrotoxicity. Free Radic Biol Med 2006; 40(9):1564-1577.
(52) Sasada T, Nakamura H, Ueda S, Iwata S, Ueno M, Takabayashi A, Yodoi J: Secretion of thioredoxin enhances cellular resistance to cis-diamminedichloroplatinum (II). Antioxid Redox Signal 2000; 2(4):695-705.
(53) Jansen BA, Brouwer J, Reedijk J: Glutathione induces cellular resistance against cationic dinuclear platinum anticancer drugs. J Inorg Biochem 2002; 89(3-4):197-202.
(54) Godwin AK, Meister A, O'Dwyer PJ, Huang CS, Hamilton TC, Anderson ME: High resistance to cisplatin in human ovarian cancer cell lines is associated with marked increase of glutathione synthesis. Proc Natl Acad Sci U S A 1992; 89(7):3070-3074.
(55) Dedoussis GV, Andrikopoulos NK: Glutathione depletion restores the susceptibility of cisplatin-resistant chronic myelogenous leukemia cell lines to Natural Killer cell-mediated cell death via necrosis rather than apoptosis. Eur J Cell Biol 2001; 80(9):608-614.
(56) Troyano A, Fernandez C, Sancho P, de BE, Aller P: Effect of glutathione depletion on antitumor drug toxicity (apoptosis and necrosis) in U-937 human promonocytic cells. The role of intracellular oxidation. J Biol Chem 2001; 276(50):47107-47115.
(57) Yao KS, Godwin AK, Johnson SW, Ozols RF, O'Dwyer PJ, Hamilton TC: Evidence for altered regulation of gamma-glutamylcysteine synthetase gene expression among cisplatin-sensitive and cisplatin-resistant human ovarian cancer cell lines. Cancer Res 1995; 55(19):4367-4374.
(58) Ikeda K, Miura K, Himeno S, Imura N, Naganuma A: Glutathione content is correlated with the sensitivity of lines of PC12 cells to cisplatin without a corresponding change in the accumulation of platinum. Mol Cell Biochem 2001; 219(1-2):51-56.
(59) Yamane Y, Furuichi M, Song R, Van NT, Mulcahy RT, Ishikawa T, Kuo MT: Expression of multidrug resistance protein/GS-X pump and gamma-glutamylcysteine synthetase genes is regulated by oxidative stress. J Biol Chem 1998; 273(47):31075-31085.
(60) Freedman JH, Ciriolo MR, Peisach J: The role of glutathione in copper metabolism and toxicity. J Biol Chem 1989; 264(10):5598-5605.
(61) Holzer AK, Varki NM, Le QT, Gibson MA, Naredi P, Howell SB: Expression of the human copper influx transporter 1 in normal and malignant human tissues. J Histochem Cytochem 2006; 54(9):1041-1049.
(62) Nakayama K, Kanzaki A, Terada K, Mutoh M, Ogawa K, Sugiyama T, Takenoshita S, Itoh K, Yaegashi N, Miyazaki K, Neamati N, Takebayashi Y: Prognostic value of the Cu-transporting ATPase in ovarian carcinoma patients receiving cisplatin-based chemotherapy. Clin Cancer Res 2004; 10(8):2804-2811.
(63) Martinez-Balibrea E, Martinez-Cardus A, Musulen E, Gines A, Manzano JL, Aranda E, Plasencia C, Neamati N, Abad A: Increased levels of copper efflux transporter ATP7B are associated with poor outcome in colorectal cancer patients receiving oxaliplatin-based chemotherapy. Int J Cancer 2009; 124(12):2905-2910.
(64) Samimi G, Varki NM, Wilczynski S, Safaei R, Alberts DS, Howell SB: Increase in expression of the copper transporter ATP7A during platinum drug-based treatment is associated with poor survival in ovarian cancer patients. Clin Cancer Res 2003; 9(16 Pt 1):5853-5859.
(65) Ishida S, McCormick F, Smith-McCune K, Hanahan D: Enhancing tumor-specific uptake of the anticancer drug cisplatin with a copper chelator. Cancer Cell 2010; 17(6):574-583.
(66) Yamane Y, Furuichi M, Song R, Van NT, Mulcahy RT, Ishikawa T, Kuo MT: Expression of multidrug resistance protein/GS-X pump and gamma-glutamylcysteine synthetase genes is regulated by oxidative stress. J Biol Chem 1998; 273(47):31075-31085.
(67) Savaraj N, Wei Y, Unate H, Liu PM, Wu CJ, Wangpaichitr M, Xia D, Xu HJ, Hu SX, Tien KM: Redox regulation of matrix metalloproteinase gene family in small cell lung cancer cells. Free Radic Res 2005; 39(4):373-381.
(68) Chen J, Liao C, Mao SJ, Chen T, Weng C: A simple technique for the simultaneous determination of molecular weight and activity of superoxide dismutase using SDS-PAGE. J Biochem Biophys Methods 2001; 47(3):233-237.
(69) Hellman NE, Kono S, Mancini GM, Hoogeboom AJ, De Jong GJ, Gitlin JD: Mechanisms of copper incorporation into human ceruloplasmin. J Biol Chem 2002; 277(48):46632-46638.
(70) Nose Y, Kim BE, Thiele DJ: Ctr1 drives intestinal copper absorption and is essential for growth, iron metabolism, and neonatal cardiac function. Cell Metab 2006; 4(3):235-244.
(71) Klomp LW, Lin SJ, Yuan DS, Klausner RD, Culotta VC, Gitlin JD: Identification and functional expression of HAH1, a novel human gene involved in copper homeostasis. J Biol Chem 1997; 272(14):9221-9226.
(72) Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van GM, van Oosterom AT, Christian MC, Gwyther SG: New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92(3):205-216.
(73) Nakagawa T, Inoue Y, Kodama H, Yamazaki H, Kawai K, Suemizu H, Masuda R, Iwazaki M, Yamada S, Ueyama Y, Inoue H, Nakamura M: Expression of copper-transporting P-type adenosine triphosphatase (ATP7B) correlates with cisplatin resistance in human non-small cell lung cancer xenografts. Oncol Rep 2008; 20(2):265-270.
(74) Yamane Y, Furuichi M, Song R, Van NT, Mulcahy RT, Ishikawa T, Kuo MT: Expression of multidrug resistance protein/GS-X pump and gamma-glutamylcysteine synthetase genes is regulated by oxidative stress. J Biol Chem 1998; 273(47):31075-31085.
(75) Mulcahy RT, Bailey HH, Gipp JJ: Transfection of complementary DNAs for the heavy and light subunits of human gamma-glutamylcysteine synthetase results in an elevation of intracellular glutathione and resistance to melphalan. Cancer Res 1995; 55(21):4771-4775.
(76) Yamane Y, Furuichi M, Song R, Van NT, Mulcahy RT, Ishikawa T, Kuo MT: Expression of multidrug resistance protein/GS-X pump and gamma-glutamylcysteine synthetase genes is regulated by oxidative stress. J Biol Chem 1998; 273(47):31075-31085.
(77) Savaraj N, Wei Y, Unate H, Liu PM, Wu CJ, Wangpaichitr M, Xia D, Xu HJ, Hu SX, Tien KM: Redox regulation of matrix metalloproteinase gene family in small cell lung cancer cells. Free Radic Res 2005; 39(4):373-381.
(78) Savaraj N, Wei Y, Unate H, Liu PM, Wu CJ, Wangpaichitr M, Xia D, Xu HJ, Hu SX, Tien KM: Redox regulation of matrix metalloproteinase gene family in small cell lung cancer cells. Free Radic Res 2005; 39(4):373-381.
(79) Harris ED: Cellular copper transport and metabolism. Annu Rev Nutr 2000; 20:291-310.
(80) Freedman JH, Ciriolo MR, Peisach J: The role of glutathione in copper metabolism and toxicity. J Biol Chem 1989; 264(10):5598-5605.
(81) Reeves PG, Ralston NV, Idso JP, Lukaski HC: Contrasting and cooperative effects of copper and iron deficiencies in male rats fed different concentrations of manganese and different sources of sulfur amino acids in an AIN-93G-based diet. J Nutr 2004; 134(2):416-425.
(82) Prohaska JR, Geissler J, Brokate B, Broderius M: Copper, zinc-superoxide dismutase protein but not mRNA is lower in copper-deficient mice and mice lacking the copper chaperone for superoxide dismutase. Exp Biol Med (Maywood ) 2003; 228(8):959-966.
(83) Cobine PA, Pierrel F, Winge DR: Copper trafficking to the mitochondrion and assembly of copper metalloenzymes. Biochim Biophys Acta 2006; 1763(7):759-772.
(84) Hellman NE, Kono S, Mancini GM, Hoogeboom AJ, De Jong GJ, Gitlin JD: Mechanisms of copper incorporation into human ceruloplasmin. J Biol Chem 2002; 277(48):46632-46638.
(85) Nose Y, Kim BE, Thiele DJ: Ctr1 drives intestinal copper absorption and is essential for growth, iron metabolism, and neonatal cardiac function. Cell Metab 2006; 4(3):235-244.
(86) Hellman NE, Kono S, Mancini GM, Hoogeboom AJ, De Jong GJ, Gitlin JD: Mechanisms of copper incorporation into human ceruloplasmin. J Biol Chem 2002; 277(48):46632-46638.
(87) Nose Y, Kim BE, Thiele DJ: Ctr1 drives intestinal copper absorption and is essential for growth, iron metabolism, and neonatal cardiac function. Cell Metab 2006; 4(3):235-244.
(88) Godwin AK, Meister A, O'Dwyer PJ, Huang CS, Hamilton TC, Anderson ME: High resistance to cisplatin in human ovarian cancer cell lines is associated with marked increase of glutathione synthesis. Proc Natl Acad Sci U S A 1992; 89(7):3070-3074.
(89) Dedoussis GV, Andrikopoulos NK: Glutathione depletion restores the susceptibility of cisplatin-resistant chronic myelogenous leukemia cell lines to Natural Killer cell-mediated cell death via necrosis rather than apoptosis. Eur J Cell Biol 2001; 80(9):608-614.
(90) Troyano A, Fernandez C, Sancho P, de BE, Aller P: Effect of glutathione depletion on antitumor drug toxicity (apoptosis and necrosis) in U-937 human promonocytic cells. The role of intracellular oxidation. J Biol Chem 2001; 276(50):47107-47115.
(91) Yao KS, Godwin AK, Johnson SW, Ozols RF, O'Dwyer PJ, Hamilton TC: Evidence for altered regulation of gamma-glutamylcysteine synthetase gene expression among cisplatin-sensitive and cisplatin-resistant human ovarian cancer cell lines. Cancer Res 1995; 55(19):4367-4374.
(92) Ikeda K, Miura K, Himeno S, Imura N, Naganuma A: Glutathione content is correlated with the sensitivity of lines of PC12 cells to cisplatin without a corresponding change in the accumulation of platinum. Mol Cell Biochem 2001; 219(1-2):51-56.
(93) Klomp AE, Tops BB, Van D, I, Berger R, Klomp LW: Biochemical characterization and subcellular localization of human copper transporter 1 (hCTR1). Biochem J 2002; 364(Pt 2):497-505.
(94) Hassett R, Kosman DJ: Evidence for Cu(II) reduction as a component of copper uptake by Saccharomyces cerevisiae. J Biol Chem 1995; 270(1):128-134.
(95) Georgatsou E, Mavrogiannis LA, Fragiadakis GS, Alexandraki D: The yeast Fre1p/Fre2p cupric reductases facilitate copper uptake and are regulated by the copper-modulated Mac1p activator. J Biol Chem 1997; 272(21):13786-13792.
(96) Gitlin JD: Wilson disease. Gastroenterology 2003; 125(6):1868-1877.
(97) Chakravarty K, Wu SY, Chiang CM, Samols D, Hanson RW: SREBP-1c and Sp1 interact to regulate transcription of the gene for phosphoenolpyruvate carboxykinase (GTP) in the liver. J Biol Chem 2004; 279(15):15385-15395.
(98) Puig S, Lee J, Lau M, Thiele DJ: Biochemical and genetic analyses of yeast and human high affinity copper transporters suggest a conserved mechanism for copper uptake. J Biol Chem 2002; 277(29):26021-26030.
(99) Nakajima O, Nakamura F, Yamashita N, Tomita Y, Suto F, Okada T, Iwamatsu A, Kondo E, Fujisawa H, Takei K, Goshima Y: FKBP133: a novel mouse FK506-binding protein homolog alters growth cone morphology. Biochem Biophys Res Commun 2006; 346(1):140-149.
(100) Kelland L: The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer 2007; 7(8):573-584.
(101) Stewart DJ: Mechanisms of resistance to cisplatin and carboplatin. Crit Rev Oncol Hematol 2007; 63(1):12-31.
(102) Ishikawa T, li-Osman F: Glutathione-associated cis-diamminedichloroplatinum(II) metabolism and ATP-dependent efflux from leukemia cells. Molecular characterization of glutathione-platinum complex and its biological significance. J Biol Chem 1993; 268(27):20116-20125.
(103) Minamino T, Tamai M, Itoh Y, Tatsumi Y, Nomura M, Yokogawa K, Suzuki H, Sugiyama Y, Ohshima T, Miyamoto K: In vivo cisplatin resistance depending upon canalicular multispecific organic anion transporter (cMOAT). Jpn J Cancer Res 1999; 90(10):1171-1178.
(104) Ishikawa T, li-Osman F: Glutathione-associated cis-diamminedichloroplatinum(II) metabolism and ATP-dependent efflux from leukemia cells. Molecular characterization of glutathione-platinum complex and its biological significance. J Biol Chem 1993; 268(27):20116-20125.
(105) Cole SP, Sparks KE, Fraser K, Loe DW, Grant CE, Wilson GM, Deeley RG: Pharmacological characterization of multidrug resistant MRP-transfected human tumor cells. Cancer Res 1994; 54(22):5902-5910.
(106) Lai GM, Ozols RF, Young RC, Hamilton TC: Effect of glutathione on DNA repair in cisplatin-resistant human ovarian cancer cell lines. J Natl Cancer Inst 1989; 81(7):535-539.
(107) Song IS, Tatebe S, Dai W, Kuo MT: Delayed mechanism for induction of gamma-glutamylcysteine synthetase heavy subunit mRNA stability by oxidative stress involving p38 mitogen-activated protein kinase signaling. J Biol Chem 2005; 280(31):28230-28240.
(108) Hartwig A: Zinc finger proteins as potential targets for toxic metal ions: differential effects on structure and function. Antioxid Redox Signal 2001; 3(4):625-634.
(109) Predki PF, Sarkar B: Effect of replacement of "zinc finger" zinc on estrogen receptor DNA interactions. J Biol Chem 1992; 267(9):5842-5846.
(110) Thiesen HJ, Bach C: Determination of DNA binding specificities of mutated zinc finger domains. FEBS Lett 1991; 283(1):23-26.
(111) Heredia J, Crooks M, Zhu Z: Phosphorylation and Cu+ coordination-dependent DNA binding of the transcription factor Mac1p in the regulation of copper transport. J Biol Chem 2001; 276(12):8793-8797.
(112) Aiba I, Hossain A, Kuo MT: Elevated GSH level increases cadmium resistance through down-regulation of Sp1-dependent expression of the cadmium transporter ZIP8. Mol Pharmacol 2008; 74(3):823-833.
(113) Nicolas M, Noe V, Jensen KB, Ciudad CJ: Cloning and characterization of the 5'-flanking region of the human transcription factor Sp1 gene. J Biol Chem 2001; 276(25):22126-22132.
(114) Bird AJ, McCall K, Kramer M, Blankman E, Winge DR, Eide DJ: Zinc fingers can act as Zn2+ sensors to regulate transcriptional activation domain function. EMBO J 2003; 22(19):5137-5146.
(115) Dhanasekaran M, Negi S, Sugiura Y: Designer zinc finger proteins: tools for creating artificial DNA-binding functional proteins. Acc Chem Res 2006; 39(1):45-52.
(116) Aida T, Takebayashi Y, Shimizu T, Okamura C, Higasimoto M, Kanzaki A, Nakayama K, Terada K, Sugiyama T, Miyazaki K, Ito K, Takenoshita S, Yaegashi N: Expression of copper-transporting P-type adenosine triphosphatase (ATP7B) as a prognostic factor in human endometrial carcinoma. Gynecol Oncol 2005; 97(1):41-45.
(117) Nakayama K, Kanzaki A, Terada K, Mutoh M, Ogawa K, Sugiyama T, Takenoshita S, Itoh K, Yaegashi N, Miyazaki K, Neamati N, Takebayashi Y: Prognostic value of the Cu-transporting ATPase in ovarian carcinoma patients receiving cisplatin-based chemotherapy. Clin Cancer Res 2004; 10(8):2804-2811.
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