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研究生:廖軒芸
研究生(外文):Hsuan-Yun Liao
論文名稱:探討CCTβ在抗藥性癌症細胞中過量表現所造成之抗藥性機制之研究
論文名稱(外文):Exploring Mechanisms of Multi-Drug Resistance in Cancer Cells Mediated by CCTβ Overexpression
指導教授:梁博煌
指導教授(外文):Po-Huang Liang
口試委員:陳瑞華蕭宏昇
口試委員(外文):Ruey-Hwa ChenHong-Shen Hsiao
口試日期:2014-07-11
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:生化科學研究所
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2014
畢業學年度:102
語文別:英文
論文頁數:110
中文關鍵詞:多重抗藥性藥物運輸蛋白
外文關鍵詞:CCTβchaperoninβ-cateninABC transporterMDRXIAPBcl2
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在許多造成抗藥性的原因中,我們發現一個幫助細胞內蛋白折疊的Chaperonin containing t-complex polypeptide 1 (CCT)中的β次單元在具有抗藥性的癌細胞中有過量表現的情況,且在過度表現CCTβ的細胞中發現MDR1的表現量上升。然而,CCTβ過量表現造成抗藥性的機制卻不完全瞭解。因此在本論文中,首先,進一步探討是否除了MDR1的表現量上升之外,有其他ABC transporters也有表現,結果發現在臨床上被研究較多的MDR1、MRP1和BCRP在具有抗藥性的和CCTβ過量表現的MCF7細胞中都有增加表現的情形。而且,隨著抑制CCTβ在細胞中的表現,也發現到這些ABC transporters也有降低表現的情形。考慮到有些文獻顯示這些ABC transporters的蛋白質表現量和功能(其運輸藥物通過細胞膜的能力)並不一定成正比,因此進一步的去分析ABC transporters的功能在CCTβ表現量變化後的影響。發現到不論在具有抗藥性的細胞或是MCF7過量表現CCTβ的細胞中,這些ABC transporters的運輸藥物的能力都有增加,而且抑制CCTβ表現的細胞中也發現到ABC transporters在功能上也是有下降的。重要的是,一個在核內還未被確認出是哪種轉譯後修飾過的β-catenin被發現為CCTβ和ABC transporters表現量之間的調控分子,隨著CCTβ的表現量上升或下降,此種β-catenin的表現量也會跟著上升或下降。許多文獻也顯示β-catenin的活化確實會使ABC transporters的表現量上升 [1-3]。綜合這些結果顯示:CCTβ可能藉由調節β-catenin進而調控了ABC transporters的蛋白質表現量和功能而導致了多重抗藥性的產生。
  除了ABC transporters之外,也有其他機制是會導致細胞具有抗藥性,包括:促進細胞存活和抗凋亡等等。抗凋亡Bcl2蛋白可以經由抑制cytocrome C從粒線體外膜釋出的機制而抑制細胞凋亡的進行,此蛋白在不論是在馴化後具有抗藥性的細胞或者是MCF7過量表現CCTβ的細胞中都可以發現到有表現量升高的情形。再者,在本篇研究中,XIAP和CCTβ之間的直接交互作用在被馴化後的7TR抗藥性細胞中被發現。更進一步發現到在MCF7中過量表現CCTβ的細胞中XIAP也有過量表現的情形,而且隨著抑制CCTβ表現也可以發現XIAP的表現量跟著下降。然而,在被馴化具有抗藥性的7TR細胞還有MCF7中過量表現CCTβ的細胞中,caspase7和活化態的caspase7的表現量卻是上升的。因此,綜合這些結果,CCTβ藉由穩定XIAP來和活化態的Caspase7形成XIAP:p12/p19-caspase7 複體以防止細胞凋亡,因此使得細胞具有抗藥性。
  整體而言,這些研究闡述了CCTβ過量表現的抗藥性細胞用於產生抗藥性的可能機制,其中包括了:CCTβ藉由調控β-catenin而影響到ABC transporters的表現和功能增進、anti-apoptotic Bcl2的表現量增加而防止經由粒線體的胞內凋亡機制,還有提高XIAP表現量而使XIAP和活化的Caspase7結合而中止下游細胞凋亡的產生。這些結果增進了我們對多重機制共同造成抗藥性的了解,其中這些參與在形成抗藥性機制而且和CCTβ有交互作用的蛋白,在之後可以做為抗癌藥物設計的目標。


Among the mechanisms causing drug resistance, the β subunit of chaperonin containing t-complex 1 (CCT), a molecular chaperonin that facilitates protein folding in eukaryotic cytosol, has been found up-regulated in drug resistant cancer cell lines as well as MDR1. However, the mechanisms underlying CCTβ expression and MDR1 expression are not fully understood. In this thesis, first of all, we examined the other ABC transporters besides MDR1 and found the expression levels of three clinically studied MDR1, MRP1, and BCRP have been increased by overexpressing CCTβ and decreased by knockdown of CCTβ. Considering that the pumping efficiency is not proportional to the expression level for these ABC transporters, we further examined their functional levels. We found the functional levels of three ABC transporters were elevated in drug resistant cell lines as well as in CCTβ-overexpression cell lines but reduced in CCTβ-knockdown cell lines. Importantly, a post-translationally modified form of β-catenin in nucleus was found to be mediated by the expression level of CCTβ and regulate the expressions of ABC transporters. In addition, the expression of ABC transporters has been related to transcription activity of β-catenin [1-3]. These results indicate that CCTβ can regulate protein expression and function of ABC transporters via β-catenin.
Furthermore, apart from ABC transporters, increasing survival signaling and anti-apoptotic signaling cause increased survival rates and chemoresistance in cancer cells. First, anti-apoptotic protein Bcl2, which participates in preventing the release of cytochrome C from mitochondria, was shown to be overexpressed in drug resistant 7TR and CCT-β overexpressed MCF-7. Moreover, in this study, the interaction between XIAP and CCTβ was identified in 7TR, and XIAP overexprssion was identified in MCF7 overexpressing CCTβ cell line. On the other hand, knockdown of CCTβ decreased the expression of XIAP. However, caspase7 and cleaved caspase7 were found up-regulated in 7TR drug resistant cells and CCTβ-overexpressed MCF7 cells. These results indicate that CCTβ interacts and stabilizes XIAP from degradation, leading to the formation of XIAP: p12/p19-caspase7 complex to prevent cell death.
In summary, these studies explored the possible mechanisms of drug resistance originated from CCTβ overexpression, which include β-catenin-mediated expressional and functional up-regulation of ABC transporters, increase of anti-apoptotic Bcl2 to prevent cytochrome c-mediated apoptosis, and raise of XIAP to form complexes with caspase 7 to prevent apoptosis. These results enhance our understanding in drug resistance caused by multiple causes. The proteins involved in the drug resistance or those interacting with CCTβ could be valuable targets for cancer drug design.


TABLE of CONTENTS
中文摘要 4
ABSTRACT 6
ABBREVIATIONS 8
(1) INTRODUCTION 11
1.1 Chaperonin containing t-complex polypeptide 1(CCT) 11
1.1.1 Sequence divergence 11
1.1.2 ATP-driven chaperonin 12
1.1.3 Structure and the content of subunits 12
1.1.4 Substrate binding specificity 13
1.1.5 Tumorigenesis 14
1.2 Multi-drug resistance (MDR) 16
1.2.1 Classification of ABC transporters 17
1.2.2 Structures of ABC transporters 18
1.2.3 Three efflux pumps in cancers 19
1.3 Wnt signaling and β-catenin 22
1.3.1 The canonical Wnt signaling 23
1.3.1.1 Wnt-off: β-catenin degradation 23
1.3.1.2 Wnt-On: β-catenin stabilization 24
1.3.2 Lymphoid-enhancing factor/T-cell factors (LEF/TCFs) 26
1.3.3 β-catenin associated co-repressors and co-activators 27
1.3.4 β-catenin in drug resistance and tumor 28
1.4 The present work 30
(2)MATERIALS AND METHODS 32
2.1 Cell culture and cell lines 32
2.2 Stable cell line generation and infection 33
2.3 Total protein lysate preparation and the isolation of cytoplasmic and nuclear fraction 33
2.4 Western bloting and antibodies 35
2.5 Co-immunoprecipitation (Co-IP) 36
2.6 Drug-exporting efficiency of ABC transporters 37
2.7 Drug sensitivity assay 39
2.8 mRNA expression analysis using RT-PCR 39
(3) RESULTS 41
3.1 Overexpression of CCTβ confers drug resistance in cancer cell lines and patients 41
3.2 CCTb regulates protein expression and function of the drug efflux pumps 41
3.3 CCTβ regulates ABC pumps via β-catenin 43
3.4 CCTβ prevents β-catenin from degradation in cytosol, leading to its translocation into nucleus during drug resistance development 45
3.5 CCTb-dependent multidrug resistance is only minimally caused by Akt signaling 46
3.6 CCTb-dependent multidrug resistance is driven by Bcl2 anti-apoptotic signaling mediated by β-catenin or phosphatases 47
3.7 CCTb regulates XIAP-dependent anti-apoptotic signaling 48
3.8 Balance of TRiC/CCT from altering expression of CCTb 49
(4) DISCUSSIONS 51
REFERENCE 57
SUPPLEMENTARY 101
APPENDIX 107


REFERENCE
1.Chikazawa, N. et al., Inhibition of Wnt signaling pathway decreases chemotherapy-resistant side-population colon cancer cells. Anticancer Res. , 2010. 30(6):2041-8.
2.Shen, D.-Y. et al., Inhibition of Wnt&;#8260;b-catenin signaling downregulates P-glycoprotein and reverses multi-drug resistance of cholangiocarcinoma. Cancer Sci. , 2013. 104(10):1303-8.
3.Zinzi, L. et al., ABC transporters in CSCs membranes as a novel target for treating tumour relapse. Front. Pharmacol., 2014.
4.Lin, Y.-F. et al., Targeting the XIAP/caspase-7 complex selectively kills caspase-3–deficient malignancies. J Clin Invest., 2013. 123(9):3861-75. .
5.Tyedmers, J. et al., Cellular strategies for controlling protein aggregation. Nat Rev Mol Cell Biol., 2010. 11(11):777-88.
6.Bigotti, M.G. et al., Chaperonins: The hunt for the Group II mechanism. Arch Biochem Biophys., 2008. 474(2):331-9. .
7.Horwich, A.L. et al., Two Families of Chaperonin: Physiology and Mechanism. Annu Rev Cell Dev Biol. , 2007. 23:115-45.
8.Booth, C.R. et al., Mechanism of lid closure in the eukaryotic chaperonin TRiC/CCT. Nat Struct Mol Biol., 2008. 15(7):746-53.
9.Cong, Y. et al., Symmetry-free cryo-EM structures of the chaperonin TRiC along its ATPase-driven conformational cycle. EMBO J. , 2012. 31(3):720-30.
10.Archibald, J.M. et al., Gene Duplication and the Evolution of Group II Chaperonins: Implications for Structure and Function. 2001.
11.Feldman, D.E. et al., Tumorigenic Mutations in VHL Disrupt Folding In Vivo by Interfering with Chaperonin Binding. Mol Cell. , 2003. 12(5):1213-24.
12.Munoz, I.G. et al., Crystal structure of the open conformation of the mammalian chaperonin CCT in complex with tubulin. Nat Struct Mol Biol., 2011. 18(1):14-9.
13.Spiess, C. et al., Identification of the TRiC/CCT Substrate Binding Sites Uncovers the Function of Subunit Diversity in Eukaryotic Chaperonins. Mol Cell. , 2006. 24(1):25-37.
14.Suwon Kim. et al., Cystosolic chaperonin subunits have a conserved ATPase domain but diverged polypeptide-binding domains. Trends Biochem Sci. , 1994. 19(12):543-8.
15.Ditzel, L. et al., Crystal Structure of the Thermosome, the Archaeal Chaperonin and Homolog of CCT. Cell, 1998. 93(1):125-38.
16.Zhang, J. et al., Mechanism of folding chamber closure in a group II chaperonin. Nature, 2010. 463(7279): 379–383.
17.Kabir, M.A. et al., Functional Subunits of Eukaryotic Chaperonin CCT/TRiC in Protein Folding. Journal of Amino Acids, 2011.
18.Melki, R. et al., Review: Nucleotide-Dependent Conformational Changes of the Chaperonin Containing TCP-11. Journal of Structural Biology, 2001. 135, 170–175.
19.Christoph Spiess A. S. et al., Stefanie Reissmann and Judith Frydman, Mechanism of the eukaryotic chaperonin: protein folding in the chamber of secrets. Trends Cell Biol. , 2004. 14(11):598-604.
20.Lin, P. et al., The unique hetero-oligomeric nature of the subunits in the catalytic cooperativity of the yeast Cct chaperonin complex. Proc Natl Acad Sci U S A. , 1997. 94(20): 10780–10785.
21.Grantham J. et al., Folding No Effect upon the Rates of b-Actin or a
Eukaryotic Chaperonin with Antibody Has No Effect upon the Rates of b-Actin or a-tubulin folding. 2000.
22.Martin-Benito J. et al., structure of eukaryotic prefoldin and of its complexes with unfoled actin and the cytosolic chaperonin CCT . EMBO J. , 2002. 21(23):6377-86.
23.EJ M. et al., Modeling of possible subunit arrangements in the eukaryotic chaperonin TRiC. Protein Sci. , 2006. 15(6):1522-6.
24.Mart&;#305;’n-Benito J. et al., The inter-ring arrangement of the cytosolic chaperonin CCT. EMBO Rep., 2007. 8(3): 252–257.
25.Yam A. et al., Defining the TRiC/CCT interactome links chaperonin function to stabilization of newly made proteins with complex topologies. Nat Struct Mol Biol., 2008. 15(12):1255-62.
26.Douglas N. R. et al., Dual Action of ATP Hydrolysis Couples Lid Closure to Substrate Releaseinto the Group II Chaperonin Chamber
Cell, 2011.
27.Camasses A. et al., The CCT Chaperonin Promotes Activation of the Anaphase-Promoting Complex through the Generation of Functional Cdc20. Mol Cell., 2003. 12(1):87-100.
28.Kitamura A. et al., Cytosolic chaperonin prevents polyglutamine toxicity with altering the aggregation state. Nat Cell Biol., 2006. 8(10):1163-70.
29.Neef D. W. et al., Modulation of Heat Shock Transcription Factor 1 as a Therapeutic Target for Small Molecule Intervention in Neurodegenerative Disease. PLoS 2010. 8(1):e1000291.
30.Llorca O. et al., eukaryotic chaperonin CCT stabilizes actin and tubulin folding intermediates in open quasi-native conformations. EMBO, 2000.
31.Leitner A. et al., The Molecular Architecture of the Eukaryotic Chaperonin TRiC/CCT. Cell Structure., 2012. 20(5):814-25.
32.Hynes G. M. et al., Individual Subunits of the Eukaryotic cytosolic chaperonin mediate interactions with binding sites located on subdomains of beta-catenin. J Biol Chem., 2000. 275(25):18985-94.
33.Llorca O. et al., Eukaryotic type II chaperonin CCT interactswith actin through specific subunits. nature, 1999.
34.Rommelaere H. et al., The Cytosolic Class II Chaperonin CCT Recognizes Delineated Hydrophobic Sequences in Its Target Proteins. Biochemistry. , 1999. 38(11):3246-57.
35.Huang H. C. et al., Evidence that Mitotic Exit Is a Better Cancer Therapeutic Target Than Spindle Assembly. Cell 2009.
36.Nowak. M. A. et al., The role of chromosomal instability in tumor initiation. Proc Natl Acad Sci U S A. , 2002. 99(25):16226-31.
37.Melki R. et al., Cytoplasmic chaperonin containing TCP-1: structural and functional characterization. Biochemistry. , 1997. 36(19):5817-26.
38.WON K. A. et al., Maturationof human cyclin E requires the function of eukaryotic chaperonin CCT. Mol Cell Biol., 1998. 18(12): 7584–7589.
39.Nibbe R. K. et al., Discovery and Scoring of Protein Interaction Subnetworks Discriminative of Late Stage Human Colon Cancer. Mol Cell Proteomics. , 2009. 8(4):827-45.
40.Yokota S.-i. et al, Increased expression of cytosolic chaperonin CCT in human hepatocellular and colonic carcinoma. Cell Stress Chaperones. , 2001. 6(4):345-50.
41.Alldinger et al., Gene expression analysis of pancreatic cell lines reveals genes overexpressed in pancreatic cancer. Pancreatology, 2005.
42.Cimmino F. et al., Comparative proteomic expression profile in all trans retinoic acid differentiated neuroblastoma cell line. J Proteome Res. , 2006. 6(7):2550-64.
43.Lin, Y.-F. et al., Intracellular beta-tubulin/chaperonin containing TCP1-beta complex serves as a novel chemotherapeutic target against drug-resistant tumors. Cancer Res. , 2007. 69(17):6879-88.
44.Melville et al., The Hsp70 and TRiC/CCT Chaperone Systems Cooperate In Vivo To Assemble the Von Hippel Lindau Tumor Suppressor Complex. Mol Cell Biol., 2003. 23(9):3141-51.
45.Ohh, M. et al., Ubiquitination of hypoxia-inducible factor requires direct binding to the b-domain of the von Hippel–Lindau protein. Nat Cell Biol. , 2000. 2(7):423-7.
46.William G. Kaelin et al., Molecular bosis of the VHL hereditary cancer syndrome. NatureNat Rev Cancer., 2002. 2(9):673-82.
47.Holohan C. et al., Cancer drug resistance: an evolving paradigm. Nat Rev Cancer. , 2013. 13(10):714-26.
48.Glasspool R. et al., Epigenetics as a mechanism driving polygenic clinical drug resistance. British Journal of Cancer 2006.
49.Curtis Balch P. et al., The epigenetics of ovarian cancer drug resistance and resensitization. American Journal of Obstetrics and Gynecology, 2004.
50.Fojo T. et al., Multiple paths to a drug resistance phenotype: Mutations, translocations, deletions and ampli&;#64257;cation of coding genes or promoter regions, epigenetic changes and microRNAs. Drug Resist Updat. , 2007. 10(1-2):59-67.
51.Baylin S. B. et al., Resistance, epigenetics and the cancer ecosystem. Nat Med., 2011. 17(3):288-9. .
52.Wilting R. H. et al., Epigenetic mechanisms in tumorigenesis, tumor cell heterogeneity and drug resistance. Elsevier, 2012.
53.Fletcher J. I. et al., ABC transporters in cancer: more than just drug efflux pumps. Nature 2010.
54.Zhou, W. et al., NEK2 Induces Drug Resistance Mainly through Activation of Ef&;#64258;ux Drug Pumps and Is Associated with Poor Prognosis in Myeloma and Other Cancers. Cancer Cell., 2013. 23(1):48-62.
55.Moitra K. et al., Multidrug Efflux pumps and Cancer Stem Cells: insights into Multidrug Resistance and Therapeutic Development. Clin Pharmacol Ther., 2011. 89(4):491-502. .
56.Settleman A. S. et al., EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 2010.
57.Natarajan K. et al., Role of breast cancer resistance protein (BCRP/ABCG2) in cancer drug resistance. Biochem Pharmacol., 2012. 83(8):1084-103. .
58.Pulford J. D. et al., The Glutathione S-Transferase Supergene Family: Regulation of GST* and the Contribution of the lsoenzymes to Cancer Chemoprotection and Drug Resistance. Critical Reviews in Biochernisty and Molecular Biology, 1995.
59.SYNOLD T. W. et al., The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux. Nat Med. , 2001. 7(5):584-90.
60.Shackelford D. B. et al., LKB1 Inactivation Dictates Therapeutic Response of Non-Small Cell Lung Cancer to the Metabolism Drug Phenformin. Cancer Cell. , 2013. 23(2):143-58.
61.Deenen M. J. et al., Part 2: pharmacogenetic variability in drug transport and phase I anticancer drug metabolism. Oncologist. , 2011. 16(6):820-34.
62.Eliopoulos A. et al., The control of apoptosis and drug resistance in ovarian cancer. Oncogene, 1995. 11(7):1217-28.
63.McCurrach et al., bax-deficiency promotes drug resistance and oncogenic transformation by attenuating p53 dependent apoptosis. Proc Natl Acad Sci U S A., 1997. 94(6): 2345–2349.
64.Tsuruo T. et al., Molecular targeting therapy of cancer: drug resistance, apoptosis and survival signal. Cancer Sci. , 2003. 94(1):15-21.
65.Fink D. et al., The Role of DNA Mismatch Repair in Platinum Drug Resistance. Cancer Res., 1996. 56(21):4881-6.
66.Lord C. et al., The DNA damage response and cancer therapy. Nature 2012. 481:287-294.
67.J. Deans A. et al., DNA interstrand crosslink repair and cancer. Nature 2011. 11:467-480.
68.Curtin N.J. et al., DNA repair dysregulation from cancer driver to therapeutic target. Nat Rev Cancer. , 2012. 12(12):801-17.
69.Wouters M. D. et al., MicroRNAs, the DNA damage response and cancer. Mutat Res. , 2011. 717(1-2):54-66. .
70.Griffin J. D. et al., Resistance to targeted therapy in leukaemia. Lancet. , 2002. 359(9305):458-9.
71.Dean M. et al., ABC Transporters, Drug Resistance, and Cancer Stem Cells. J Mammary Gland Biol Neoplasia. , 2009. 14(1):3-9.
72.Wang, Z. et al., Targeting miRNAs involved in cancer stem cell and EMT regulation: An emerging concept in overcoming drug resistance. Drug Resist Updat. , 2010. 13(4-5):109-18.
73.Clevers H. et al., The cancer stem cell: premises, promises and challenges. Nat Med. , 2011. 17(3):313-9.
74.Hanahan D. et al., Hallmarks of Cancer: The Next Generation. Cell, 2011.
75.Baguley B. C. et al., Multiple Drug Resistance Mechanisms in Cancer. Mol Biotechnol. , 2010. 46(3):308-16.
76.Chaves C. et al., Human ABC Transporters at blood-CNS Interfaces as Determinants of CNS Drug Penetration. Curr Pharm Des., 2014. 20(10):1450-62.
77.Dutheil F. et al., ABC transporters and cytochromes P450 in the human central nervous system: influence on brain pharmacokinetics and contribution to neurodegenerative disorders. Expert Opin Drug Metab Toxicol, 2010. 6(10):1161-1174.
78.Wager T. T. et al., Strategies to optimize the brain availability of central nervous system drug candidates. Expert Opin Drug Discov. , 2011. 6(4):371-81. .
79.Voloshyna I. et al., The ABC transporters in lipid &;#64258;ux and atherosclerosis. Prog Lipid Res., 2011. 50(3):213-24.
80.Tarling E. J. et al., Role of ABC transporters in lipid transport and human disease. Trends Endocrinol Metab., 2013. 24(7):342-50.
81.Dean M. et al., The human ATP-binding cassette (ABC) transporter superfamily. Genome Res., 2001. 11(7):1156-66.
82.Annilo M. D. et al., Evolution of the ATP-Binding Cassette (ABC Transporter Superfamily in Vertebrates. Ann Rev Hum Genet Genome, 2005.
83.Aleksandrov A. A. et al., CFTR (ABCC7) is a hydrolyzable-ligand-gated channel. Pflugers Arch, 2007. 453(5):693-702. .
84.Kemp S. et al., ABCD1 Mutations and the X-linked Adrenoleukodystrophy Mutation Database: Role in Diagnosis and Clinical Correlations. Hum Mutat., 2001. 18(6):499-515.
85.Dean M. et al., Tumour stem cells and drug resistance. Nat Rev Cancer. , 2005. 5(4):275-84.
86.ZE, s. et al., The Mechanism of Action of Multidrug-Resistance Linked P-Glycoprotein. J Bioenerg Biomembr., 2001. 33(6):481-91.
87.Leslie E. M. et al., Multidrug resistance proteins: role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense. Toxicol Appl Pharmacol. , 2005. 204(3):216-37.
88.Ambudkar S. V. et al., Biochemical, cellular, and pharmacological aspects of the multidrug transporter. Pharmacol. Toxicol. , 1999. 39:361-98.
89.Choi, C. H. et al., ABC transporters as multidrug resistance mechanisms and the development of chemosensitizers for their reversal. Cancer Cell Int., 2005.
90.Amiri-Kordestania L. et al., Targeting MDR in Breast and Lung Cancer: Discriminating its Potential Importance from the Failure of Drug Resistance Reversal Studies. Drug Resist Updat. , 2012. 15(1-2):50-61.
91.Walsh N. et al., Expression of multidrug resistance markers ABCB1 (MDR-1/P-gp) and ABCC1 (MRP-1) in renal cell carcinoma. BMC Urology, 2009.
92.Han K. et al., Expression of Functional Markers in Acute Nonlymphoblastic Leukemia. Acta Hamatologica, 2000.
93.Zalcberg J. et al., MRP1 not MDR1 gene expression is the predominant mechanism of acquired multidrug resistance in two prostate carcinoma cell lines. Prostate Cancer Prostatic Dis. , 2000. 3(2):66-75.
94.Triller N. et al., Multidrug resistance in small cell lung cancer: Expression of P-glycoprotein, multidrug resistance protein 1 and lung resistance protein in chemo-naive patients and in relapsed disease. Lung Cancer., 2006. 54(2):235-40.
95.Nooter K. et al., The prognostic significance of expression of the multidrug resistance-associated protein (MRP) in primary breast cancer. Br J Cancer., 1997. 76(4):486-93.
96.Kelly W. K. et al., Epothilones in prostate cancer. Urologic Oncology, 2011.
97.Kruh, G.D., The MRP family of drug ef&;#64258;ux pumps. Oncogene, 2003. 22(47):7537-52.
98.Wijnholds J. et al., Multidrug resistance protein 1 protects the choroid plexus epithelium and contributes to the blood-cerebrospinal fluid barrier. J Clin Invest., 2000. 105(3):279-85.
99.Tribull T. E. et al., The multidrug resistance-associated protein 1 transports methoxychlor and protects the seminiferous epithelium from injury. Toxicol Lett., 2003. 142(1-2):61-70.
100.Ortega A. L. et al., Glutathione in Cancer Cell Death. Cancers, 2011.
101.Deeley S. P. et al., Transport of glutathione and glutathione conjugates by MRP1. Trends Pharmacol Sci., 2008. 27(8):438-46.
102.Kim M. F. et al., Handbook of Experimental Pharmacology : Drug transporters. Springer, 2011. 201.
103.Doyle L. A. et al., A multidrug resistance transporter from human MCF-7 breast cancer cells. Proc Natl Acad Sci U S A. , 1998. 95(26): 15665–15670.
104.Maliepaard M. et al., Subcellular Localization and Distribution of the Breast Cancer Resistance Protein Transporter in Normal Human Tissues. Cancer Res., 2001. 61(8):3458-64.
105.Staud F. et al., Breast cancer resistance protein (BCRP/ABCG2). Int J Biochem Cell Biol. , 2005. 37(4):720-5.
106.Morisaki K. et al., Single nucleotide polymorphisms modify the transporter activity of ABCG2. Cancer Chemother Pharmacol., 2005. 56(2):161-72.
107.Haraguchi N. et al., Characterization of a side population of cancer cells from
human gastrointestinal system. Stem Cells. , 2006. 24(3):506-13.
108.Weinstein et al., Relationship of the expression of the multidrug resistance gene product (P-glycoprotein) in human colon carcinoma to local tumor aggressiveness and lymph node metastasis. Cancer Res., 1991. 51(10):2720-6.
109.Takara K. et al., Digoxin Up-Regulates MDR1 in Human Colon Carcinoma Caco-2 Cells. Biochem Biophys Res Commun., 2002. 292(1):190-4.
110.Ohtsuki S. et al., Correlation of induction of ATP binding cassette transporter A5 (ABCA5) and ABCB1 mRNAs with differentiation state of human colon tumor. Biol Pharm Bull., 2007. 30(6):1144-6.
111.Oda Y. et al., ATP-binding cassette superfamily transporter gene expression in human soft tissue sarcomas. Int J Cancer., 2005. 114(6):854-62.
112.Zochbauer-Muller et al., P-glycoprotein and MRP1 expression in axillary lymph node metastases of breast cancer patients. Anticancer Res. , 2001. 21(1A):119-24.
113.List A. F. et al., Overexpression of the Major Vault Transporter Protein Lung-Resistance Protein Predicts Treatment Outcome in Acute Myeloid Leukemia Blood, 1996. 87(6):2464-9.
114.Nusse C. Y. et al., The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol. , 2004. 20:781-810.
115.Clevers H. et al., Wnt/β-Catenin Signaling in Development and Disease. Cell 2006. 127(3):469-80.
116.Clevers T. R. et al., Wnt signalling in stem cells and cancer. Nature 2005. 434(7035):843-50.
117.Katoh M. et al., WNT/PCP signaling pathway and human cancer Oncol Rep. , 2005. 14(6):1583-8.
118.Kohn A. D. et al., Wnt and calcium signaling: beta-Catenin-independent pathways. Cell Calcium., 2005. 38(3-4):439-46.
119.MacDonald B. T. et al., Wnt/b-Catenin Signaling: Components, Mechanisms, and Diseases. Dev Cell., 2009. 17(1):9-26.
120.Ikeda S. et al., Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3beta and beta-catenin and promotes GSK 3betadependent phosphorylation of beta-catenin. EMBO J. , 1998. 17(5):1371-84.
121.Liu, C. et al., Control of beta -Catenin Phosphorylation/Degradation by a Dual-Kinase Mechanism. Cell 2002. 108(6):837-47.
122.Sakanaka et al., Bridging of b-catenin and glycogen synthase kinase-3b by Axin and inhibition of b-catenin-mediated transcription. Proc Natl Acad Sci U S A. , 1998. 95(6):3020-3.
123.Lee, E. et al., The roles of APC and Axin derived from experimental and theoretical analysis of the Wnt pathway. PLoS Biol. , 2003. 1(1):E10.
124.Mao J. et al., Low-density lipoprotein receptorrelated protein-5 binds to Axin and regulates the canonical Wnt signaling pathway. Mol Cell., 2001. 7(4):801-9.
125.Tolwinsk N. S. et al., Wg/Wnt Signal Can Be Transmittedthrough Arrow/LRP5,6 and Axin Independently of Zw3/Gsk3 Activity. Dev Cell. , 2003. 4(3):407-18.
126.KW K. et al., Lessons from hereditary colorectal cancer. Cell 1996. 87(2):159-70.
127.Rubinfeld B. et al., Binding of GSK3, to the APC-I1-Catenin Complex and Regulation of Complex Assembly. Science, 1996. 272(5264):1023-6.
128.Liu, C. et al., Control of beta-Catenin Phosphorylation/Degradation by a Dual-Kinase Mechanism. Cell, 2002. 108(6):837-47.
129.Aberle H. et al., β-catenin is a target for the ubiquitin–proteasome pathway. EMBO J. , 1997. 16(13):3797-804.
130.Kitagawa M. et al., An Fbox protein, FWD1, mediates ubiquitin-dependent proteolysis of beta-catenin. EMBO, 1999.
131.Mosimann C. et al., β-Catenin hits chromatin: regulation of Wnt target gene activation. Nat Rev Mol Cell Biol. , 2009. 10(4):276-86.
132.Major M. B. et al., Wilms tumor suppressor WTX negatively regulates WNT/beta-catenin signaling. Science, 2007. 316(5827):1043-6.
133.Schwarz-Romond T. et al., The ankyrin repeat protein Diversin recruits Casein kinase Iepsilon to the beta-catenin degradation complex and acts in both canonical Wnt and Wnt/JNK signaling. Genes Dev., 2002. 16(16):2073-84.
134.Cselenyi C. S. et al., LRP6 transduces a canonical Wnt signal independently of Axin degradation by inhibiting GSK3’s phosphorylation of beta-catenin. Proc Natl Acad Sci U S A. , 2008. 105(23):8032-7.
135.Piao S. et al., Direct inhibition of GSK3beta by the phosphorylated cytoplasmic domain of LRP6 in Wnt/beta-catenin signaling. PLoS One. , 2008. 3(12):e4046.
136.Wu, G. et al., Inhibition of GSK3 phosphorylation of beta-catenin via phosphorylated PPPSPXS motifs of Wnt coreceptor LRP6. PLoS One., 2009. 4(3):e4926.
137.E. L. et al., The roles of APC and Axin derived from experimental and theoretical analysis of the Wnt pathway. PLoS Biol. , 2003. 1(1):E10.
138.Tolwinski et al., Wg/Wnt signal can be transmitted through arrow/LRP5,6 and Axin independently of Zw3/Gsk3beta activity. Dev Cell. , 2003. 4(3):407-18.
139.Liu, X. et al., Rapid, Wnt-induced changes in GSK3beta associations that regulate betacatenin stabilization are mediated by Galpha proteins. Curr Biol., 2005. 15(22):1989-97.
140.Yamamoto H. et al., Phosphorylation of axin, a Wnt signal negative regulator, by glycogen synthase kinase-3beta regulates its stability. J Biol Chem., 1999. 274(16):10681-4.
141.MacDonald B. T. et al., Wnt/β-catenin signaling: components, mechanisms, and diseases. Dev Cell., 2009. 17(1):9-26.
142.Luo, W. et al., Protein phosphatase 1 regulates assembly and function of the b-catenin degradation complex. EMBO J., 2007. 26(6):1511-21.
143.Su, Y. et al., APC Is Essential for Targeting Phosphorylated b-Catenin to the SCFb-TrCP Ubiquitin Ligase. Mol Cell. , 2008. 32(5):652-61.
144.Xu, D. K. et al., b-Catenin destruction complex: insights and questions from a structural perspective. Oncogene, 2006. 25(57):7482-91.
145.Wu, X. et al., Rac1 activation controls nuclear localization of beta-catenin during canonical Wnt signaling. Cell, 2008. 133(2):340-53.
146.Hoppler S. et al., Wnt signalling: variety at the core. J Cell Sci. , 2007. 120(Pt 3):385-93.
147.Arce L. et al., Diversity of LEF/TCF action in development and disease. Oncogene., 2006. 25(57):7492-504.
148.Weis D. L. et al., Beta-catenin directly displaces Groucho/TLE repressors from Tcf/Lef in Wntmediated transcription activation. Nature 2005.
149.Li, F.-Q. et al., Chibby cooperates with 14–3-3 to regulate beta-catenin subcellular distribution and signaling activity. J Cell Biol. , 2008. 181(7):1141-54.
150.Tago K. i. et al., Inhibition of Wnt signaling by ICAT, a novel beta-catenin-interacting protein. Genes Dev. , 2000. 14(14):1741-9.
151.Kavanagh S. H. et al., Wnt signalling: variety at the core. J Cell Sci. , 2007. 120(Pt 3):385-93.
152.Lee, E. et al., Physiological regulation of beta-catenin stability by Tcf3 and CK1ε. J Cell Biol., 2001. 154(5): 983–994.
153.Jones S. W. et al., CK2 controls the recruitment of Wnt regulators to target genes in vivo. Curr Biol. , 2006. 16(22):2239-44.
154.Yamamoto H. et al., Sumoylation is involved in b-catenin-dependent activation of Tcf-4. EMBO J. , 2003. 22(9):2047-59.
155.Jones, K.W.a.K.A., Wnt signaling: is the party in the nucleus? Genes Dev., 2006. 20(11):1394-404.
156.Yamada T. et al., Transactivation of the Multidrug Resistance 1 Gene by T-Cell Factor 4/b-Catenin Complex in Early Colorectal Carcinogenesis. Cancer Res. , 2000. 60(17):4761-6.
157.Flahaut M. et al., The Wnt receptor FZD1 mediates chemoresistance in neuroblastoma through activation of the Wnt/b-catenin pathway. Oncogene., 2009. 28(23):2245-56.
158.Bourguignon L. Y. et al., Hyaluronan-mediated CD44 interaction with p300 and SIRT1 regulates beta-catenin signaling and NFkappaB-specific transcription activity leading to MDR1 and Bcl-xL gene expression and chemoresistance in breast tumor cells. J Biol Chem., 2009. 284(5):2657-71.
159.Hu, Y. et al., b-Catenin is essential for survival of leukemic stem cells insensitive to kinase inhibition in mice with BCR-ABL-induced chronic myeloid leukemia. Leukemia 2009. 23(1):109-16.
160.Radich J. P. et al., Gene expression changes associated with progression and response in chronic myeloid leukemia. PNAS, 2006.
161.Zhao, C. et al., Loss of b-Catenin Impairs the Renewal of Normal and CML Stem Cells In Vivo. Cancer Cell. , 2007. 12(6):528-41.
162.Ren R. et al., Mechanisms of BCR–ABL in the pathogenesis of chronic myelogenous leukaemia. Nature 2005.
163.Hughes T. et al., Monitoring CMLpatients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood 2006. 108(1):28-37.
164.Quintas-Cardama A. et al., BCR Mechanisms of Primary and Secondary Resistance to Imatinib in Chronic Myeloid Leukemia. Cancer Control., 2009. 16(2):122-31.
165.Visvader J. E. et al., Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer., 2008. 8(10):755-68.
166.Ailles L. E. et al., Cancer stem cells in solid tumors. Current Opinion in Biotechnology, 2007. 18:460–466.
167.Yeung J. et al., b-Catenin Mediates the Establishment and Drug Resistance of MLL Leukemic Stem Cells. Cancer Cell. , 2010. 18(6):606-18.
168.Sharom F. J. et al., ABC multidrug transporters: structure, function and role in chemoresistance. Pharmacogenomics, 2008. 9(1), 105–127.
169.S. L. et al., Transcriptional regulators of the human multidrug resistance 1 gene: recent views. Biochem Pharmacol. , 2002. 64(5-6):943-8.
170.Khramtsov A. I. et al., Wnt/beta-catenin pathway activation is enriched in basal-like breast cancers and predicts poor outcome. Am J Pathol., 2010. 176(6):2911-20.
171.Kobayashi M. et al., Nuclear translocation of beta-catenin in colorectal cancer. Br J Cancer. , 2000. 82(10):1689-93.
172.L Y. et al., Expression of beta-catenin by acute myeloid leukemia cells predicts enhanced clonogenic capacities and poor prognosis. Leukemia, 2006.
173.Suzuki H. et al., Frequent epigenetic inactivation of Wnt antagonist genes in breast cancer. British Journal of Cancer, 2008.
174.Chau, W. et al., c-Kit mediates chemoresistance and tumor-initiating capacity of ovarian cancer cells through activation of Wnt/b-catenin-ATP-binding cassette G2 signaling. Oncogene. , 2013. 32(22):2767-81.
175.Sinnberg T. et al., b-Catenin signaling increases during melanoma progression and promotes tumor cell survival and chemoresistance. PLoS One., 2011. 6(8):e23429.
176.Mogi M. et al., Akt signaling regulates side population cell phenotype via Bcrp1 translocation. J Biol Chem., 2003. 278(40):39068-75.
177.Wang, X. Q. et al., Octamer 4 (Oct4) Mediates Chemotherapeutic Drug Resistance in Liver Cancer Cells Through a Potential Oct4–AKT–ATP-Binding Cassette G2 Pathway. Hepatology. , 2010. 52(2):528-39.
178.Ohmichi M. et al., Mechanisms of platinum drug resistance. Trends Pharmacol Sci. , 2005. 26(3):113-6.
179.Settleman J. et al., Drugging the Bad “AKT-TOR” to Overcome TKI-Resistant Lung cancer. Cancer Cell, 2007.
180.Blagosklonny M. V. et al., Paradox of Bcl-2 (and P53): Why may apoptosis-regulating proteins be irrelevant to cell death? Bioessays., 2001. 23(10):947-53.
181.Yamamoto K. et al., BCL-2 Is Phosphorylated and inactivated by an ASK1/Jun N-terminal protein kinase pathway normally activated at G2/M. Mol Cell Biol., 1999. 19(12):8469-78.
182.Ruvolo P. et al., Phosphorylation of Bcl2 and regulation of apoptosis. Leukemia, 2001. 15(4):515-22.
183.K S. et al., Nrf2 Protein Up-regulates Antiapoptotic Protein Bcl-2 and Prevents Cellular Apoptosis. J Biol Chem. , 2012. 287(13):9873-86. .
184.Gottesman M. M. et al., Multidrug resistance in cancer: role of ATP–dependent transporters. Nat Rev Cancer., 2001. 2(1):48-58.
185.Trinidad A. G. et al., Interaction of p53 with the CCT Complex Promotes Protein Folding and Wild-Type p53 Activity. Mol Cell., 2013. 50(6):805-17.
186.Ongkeko Y. A. et al., ABCG2: the key to chemoresistance in cancer stem cells? Expert Opin Drug Metab Toxicol., 2009. 5(12):1529-42.
187.Kaye S. B. et al., Reversal of Drug Resistance in Ovarian Cancer: Where Do We Go From Here? J Clin Oncol. , 2008. 26(16):2616-8.
188.Hennessy B. T. et al., Exploiting the PI3K/AKT Pathway for Cancer Drug Discovery. Nature 2005.
189.Vivanco I. et al., The phosphatidylinositol 3-Kinase–AKT pathway in human cancer. Nat Rev Cancer., 2002. 2(7):489-501.
190.Imai Y. et al., Versatile inhibitory effects of the flavonoid-derived PI3K/Akt inhibitor, LY294002, on ATP-binding cassette transporters that characterize stem cells. Clin Transl Med., 2012. 1(1):24. .
191.Touil Y. et al., The PI3K/AKT Signaling Pathway Controls the Quiescence of the Low-Rhodamine123-Retention Cell Compartment Enriched for Melanoma Stem Cell Activity. Stem Cells. , 2013. 31(4):641-51.
192.Reed K. Y. et al., Bcl-2 family proteins and cancer. Oncogene., 2008. 27(50):6398-406.
193.Blagosklonny M. V. et al., Taxol-induced apoptosis and phosphorylation of Bcl-2 protein involves c-Raf-1 and represents a novel c-Raf-1 signal transduction pathway. Cancer Res., 1996. 56(8):1851-4.
194.Jordan M. A. et al., Microtubules and actin filaments: dynamic targets for cancer chemotherapy. Curr Opin Cell Biol., 1998. 10(1):123-30.
195.MV B. et al., Raf1/bcl2 phosphorylation: a step from microtubule damage to cell death. Cancer Res., 1997. 57(1):130-5.
196.Berrieman H. K. et al., Do beta-tubulin mutations have a role in resistance to chemotherapy? Lancet Oncol. , 2004. 5(3):158-64.
197.Giannakakou P. et al., Paclitaxel-resistant human ovarian cancer cells have mutant beta-tubulins that exhibit impaired paclitaxel-driven polymerization. J Biol Chem., 1997. 272(27):17118-25.
198.He L. et al., Mutations in beta-tubulin map to domains involved in regulation of microtubule stability in epothilone-resistant cell lines. Mol Cancer Ther., 2001. 1(1):3-10.
199.Hua, X. H. et al., Biochemical genetic analysis of indanocine resistance in human leukemia. Cancer Res., 2001. 61(19):7248-54.
200.Twiddy D. et al., Caspase7 is directly activated by the approximately 700-kDa apoptosome complex and is released as a stable XIAP-caspase-7 approximately 200-kDa complex. J Biol Chem., 2006. 281(7):3876-88.
201.Gores M. E. et al., Unshackling caspase-7 for cancer therapy. J Clin Invest., 2013. 123(9):3706-8.







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