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研究生:鍾文彬
研究生(外文):Wen-Bin Zhong
論文名稱:Lovastatin對人類甲狀腺未分化癌細胞之抗癌機轉
論文名稱(外文):Molecular Mechanisms of Lovastatin-Induced Anti-cancer Effect in Human Anaplastic Thyroid Cancer Cells
指導教授:李文森李文森引用關係張天鈞張天鈞引用關係
指導教授(外文):Wen-Sen LeeTien-Chun Chang
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:生理學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2003
畢業學年度:92
語文別:中文
論文頁數:126
中文關鍵詞:甲狀腺未分化癌Lovastatin細胞凋亡入侵性細胞再分化RhoGeranylgeranylationHMG-CoA Reductase
外文關鍵詞:Anaplastic Thyroid CancerLovastatinApoptosisinvasivenessRe-differentiationRhoGeranylgeranylationHMG-CoA Reductase
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Lovastatin 臨床上用於治療高血脂是利用其抑制mevalonate 的生合成路徑。抑制mevalonate 的生合成作用常引起抑制細胞增生和細胞凋亡。本篇論文主要研究 Lovastatin 是否會引發人類未分化甲狀腺癌細胞ARO 產生凋亡現象,進而瞭解其作用的分子機制。利用 DNA 片段化測定法與流式細胞分析法,我們發現 Lovastatin確實會引發 ARO細胞凋亡的發生,並具有濃度依賴性與處理時間依賴性。若ARO 細胞預先以cycloheximide 處理,將抑制Lovastatin誘發之凋亡作用並具濃度依賴性。這個數據顯示 Lovastatin 誘發之 ARO 細胞凋亡作用需要蛋白質的新生成。ARO 細胞處理 50 mM Lovastatin後誘發一連串的凋亡反應,包括 (依發生時間次序) cytochrome c由粒腺體釋出進入細胞質內,活化蛋白分解酵素caspase-2, -3和-9,以及 poly(ADP-ribose) polymerase (PARP) 的降解反應。然而,外加mevalonate 或 geranylgeraniol (GGOH) 則可以預防Lovastatin誘發的凋亡反應與 PARP 的降解反應發生,但farnesol (FOH) 卻無此效應。當ARO 細胞處理geranylgeranyltransferase (GGTase) 抑制劑 (GGTI-298) 阻斷geranylgeranylation作用時,亦會增加凋亡細胞的比率。這些數據暗示在Lovastatin 處理下,geranylgeranylation 作用對ARO 細胞存活的維持是必須的。為了支持這個觀點,我們證實 ARO 細胞處理 Lovastatin後,RhoA 和 Rac1之活化,由細胞質到細胞膜的易位反應強烈的被抑制 (Ras 卻無此效應)。再者,外加mevalonate 或 GGOH則可以預防 Lovastatin 對 RhoA 和 Rac1的易位反應抑制現象,外加FOH卻無此預防效應。綜合以上,我們的數據暗示,Lovastatin誘發的ARO細胞凋亡反應是透過抑制Rho家族蛋白的geranylgeranylation作用,而不是Ras家族蛋白的farnesylation作用。

Lovastatin has been used to treat hyperlipidemia through blocking the mevalonate biosynthesis pathway. Inhibition of mevalonate synthesis may result in anti-proliferation and cell apoptosis. The aim of the present study was to examine the apoptotic effect of lovastatin in human ARO cells and to delineate its molecular mechanism underlying. Using DNA fragmentation and flow cytometry analyses, we demonstrated that lovastatin induced the occurrence of apoptosis in ARO cells in a dose- and time-dependent manner. Pretreatment of ARO cells with cycloheximide (CHX) dose-dependently suppressed lovastatin-induced apoptosis, suggesting that de novo protein synthesis is required for lovastatin effect on the induction of apoptosis in ARO cells. Treatment of the cells with 50 mM lovastatin induced cytochrome c translocation from mitochondria to cytosol, increases in caspases 2, 3 and 9 activity, and poly (ADP-ribose) polymerase (PARP) degradation in a time-dependent manner. However, administration of mevalonate or geranylgeraniol (GGOH), but not farnesol (FOH), dose-dependently prevented lovastatin-induced PARP degradation and the occurrence of apoptosis, while treatment of ARO cells with geranylgeranyltransferase (GGTase) inhibitor, GGTI-298, which blocks the geranylgeranylation, induced an increase in the percentage of the apoptotic cells. These data suggest that geranylgeranylation is required for survival of the lovastatin-treated ARO cells. To support this notion, we demonstrate that treatment of the cells with lovastatin dose-dependently decreased the translocation of RhoA and Rac1, but not Ras, from cytosol to membrane fraction. Moreover, the inhibitions of lovastatin-induced membrane translocation in RhoA and Rac1 were prevented by mevalonate and GGOH, but not by FOH. In conclusion, our data suggest that lovastatin induced apoptosis in ARO cells by inhibiting protein geranylgeranylation of the Rho family, but not farnesylation of the Ras family.

目錄
內文標題 頁
第一章 緒言及文獻回顧........................................01
A. 癌症與治療................................................01
B. 甲狀腺癌..................................................03
C. 細胞凋亡..................................................05
D. 細胞分化與微絨毛結構......................................11
E. 癌細胞入侵/移動...........................................11
F. Statins與HMG-CoA reductase................................12
G. Statins與癌細胞...........................................14
H. Protein prenylation.......................................15
I. RAS 超級家族的活化........................................17
J. RAS 超級家族的功能........................................19
K. 本論文三大主題............................................23
J. 圖/表
圖1-1 細胞壞死與細胞凋亡的形態學特徵比較.....................07
圖1-2 Ras蛋白經過四道轉譯後修飾作用,使其具有細胞膜的轉位活性,並且得以執行其訊息傳遞的功能..................................16
圖1-3 Ras 的活化作用週期.....................................18
表1-1細胞凋亡與細胞壞死各種相異特質的綜合比較.................08
第二章 實驗材料與方法........................................25
A. 藥品與試劑................................................25
B. 抗體......................................................26
C. 細胞與細胞培養............................................26
D. 細胞生長度與存活度測試....................................26
E. 利用洋菜膠電泳技術分析DNA段裂.............................27
F. Caspases 活性分析 ........................................28
G. 利用流式細胞儀分析細胞凋亡................................29
(1) 細胞週期分析..............................................29
(2) Annexin V結合分析.........................................29
(3) Terminal transfer Utilizing Nick End Labeling (TUNEL) 染色測試............................................................30
H. 粒腺體內膜電位差變化之測定................................30
I. 細胞質溶液之抽取與細胞質內Cytochrome c 之測定.............31
J. 西方墨點法................................................31
K. 細胞全蛋白抽取 ...........................................32
(1) PARP 分解測試
(2) FAK與paxillin之磷酸化測試
L. 不溶性細胞微粒成份與細胞質部分之分離......................33
M. 電子顯微鏡檢查 ...........................................34
N. 甲狀腺球蛋白濃度測定......................................35
O. Matrigel 入侵試驗.........................................36
P. F-actin 染色與流式細胞儀分析..............................36
Q. 細胞附著力測試 ...........................................36

圖 2-1 MTT測試法原理..........................................27
第三章 Lovastatin誘發人類甲狀腺未分化癌細胞凋亡,過程涉及抑制蛋白分子geranylgeranylation修飾作用與蛋白新合成反應.............37
A. 中文摘要..................................................38
B. 英文摘要 (ABSTRACT)........................................39
C. 序論.......................................................41
D. 結果............................................................43
1. Lovastatin 抑制ARO細胞生長.................................43
2. Lovastatin 誘發ARO細胞產生凋亡現象.........................43
3. Lovastatin 誘發ARO細胞產生凋亡現象涉及蛋白新合成作用.......44
4. Lovastatin 誘發ARO細胞產生凋亡過程涉及cytochrome c釋出與caspases活化..................................................45
5. 抑制ARO細胞之蛋白 geranylgeranylation 與 farnesylation作用皆會引起細胞凋亡發生............................................46
6. Geranylgeraniol可避免 Lovastatin 誘發之ARO細胞凋亡.........46
7. Lovastatin 抑制 Rho 家族蛋白由細胞質活化轉位至細胞膜之作用.47
8. RhoA and RhoA kinase 是維持ARO 細胞生存所必須的分子........48
E 討論.......................................................50
F. 圖
圖3-1 Lovastatin 之化學結構..................................40
圖3-2 Mevalonate 代謝路徑....................................40
圖3-3 Lovastatin 抑制ARO細胞生長.............................55
圖3-4 Lovastatin 誘發ARO細胞 DNA 片段化與 phosphatidylserine 外翻現象........................................................56
圖3-5 Lovastatin-誘發ARO細胞凋亡需涉及蛋白質新合成作用.......57
圖3-6 Lovastatin處理後,引發ARO細胞內粒腺體cytochrome c釋出,caspases之活化與PARP被切割分解................................58
圖3-7 Prenyltransferase抑制劑引發ARO細胞凋亡.................60
圖3-8 Mevalonate與GGOH處理能預防Lovastatin-誘發ARO細胞凋亡之發生............................................................61
圖3-9 Lovastatin 抑制RhoA 與 Rac1的細胞膜的易位反應..........62
圖3-10 阻斷RhoA/RhoA kinase訊息傳遞會引發ARO細胞凋亡之發生...63
圖3-11 Lovastatin 引發ARO甲狀腺未分化癌細胞凋亡發生之可能機轉............................................................64
第四章 Lovastatin,一種3-Hydroxy-3-methylglutaryl Coenzyme A Reductase 抑制劑, 誘發人類甲狀腺未分化癌細胞分化之反應 65
A. 中文摘要..................................................66
B. 英文摘要...................................................67
C. 序論.......................................................68
D. 結果.......................................................70
1. Lovastatin誘發ARO細胞產生微絨毛結構........................70
2. Lovastatin促使ARO細胞減少甲狀腺球蛋白......................70
E. 討論.......................................................71
F. 圖.........................................................73
圖4-1 Lovastatin誘發ARO細胞表面微絨毛結構之增加 (SEM)........73
圖4-2 Lovastatin誘發ARO細胞表面微絨毛結構與細胞質分泌型微粒之增加 (TEM)......................................................74
圖4-3 Lovastatin 刺激使ARO細胞甲狀腺球蛋白分泌大幅增加.......75
圖4-4 Lovastatin 誘發ARO甲狀腺未分化癌細胞之再分化可能機轉...76
第五章 Lovastatin抑制EGF-誘發人類甲狀腺未分化癌細胞之入侵性,過程涉及抑制蛋白分子geranylgeranylation修飾作用與RhoA/ROCK訊息傳遞途徑..........................................................77
A. 中文摘要...................................................78
B. 英文摘要 (ABSTRACT)........................................80
C. 序論.......................................................82
D. 結果.......................................................85
1. Lovastatin抑制ARO 甲狀腺未分化癌細胞的EGF-誘發細胞入侵性...85
2. Geranylgeraniol 與 mevalonate能減低lovastatin對ARO細胞入侵性的抑制性效....................................................85
3. 蛋白geranylgeranylation對ARO未分化癌細胞的EGF-誘發細胞入侵性是必須的......................................................86
4. Lovastatin抑制EGF-誘發之Rho GTPases由細胞質向細胞膜上易位結合的過程........................................................86
5. Rho/ROCK訊息傳遞途徑對ARO細胞的EGF-誘發細胞入侵性是必須的..87
6. Lovastatin藉抑制RhoA/ ROCK訊息傳遞途徑而降低ARO細胞-ECM的附著力............................................................88
7. Lovastatin 對ARO細胞型態及細胞骨骼重整的影響...............89
8. Lovastatin 抑制EGF-誘發之p125FAK/paxillin活化訊息途徑......89
E. 討論.......................................................91
F. 圖.........................................................95
圖5-1 Lovastatin抑制EGF-誘發穿透Matrigel覆膜的入侵性.........95
圖5-2 Geranylgeraniol 與 mevalonate 之處理能回復被lovastatin所抑制的ARO細胞入侵性...........................................97
圖5-3 蛋白geranylgeranylation修飾作用對EGF-誘發ARO細胞入侵性是必須的........................................................98
圖5-4 Lovastatin抑制EGF-誘發ARO細胞內Rho GTPases蛋白之易位至細胞膜的反應....................................................99
圖5-5 抑制RhoA/ROCK訊息傳遞途徑會減少EGF-誘發ARO細胞入侵性作用...........................................................100
圖5-6 Lovastatin藉抑制RhoA/ROCK訊息傳遞途徑之活化來減弱ARO細胞-ECM附著力 ...................................................101
圖5-7 Lovastatin對ARO細胞型態與EGF-誘發之actin stress fiber重整的影響.......................................................103
圖5-8 Lovastatin減少細胞內FAK蛋白量,也抑制EGF-誘發FAK and paxillin之磷酸化作用.........................................104
圖5-9 Lovastatin 抑制 ARO甲狀腺未分化癌細胞移動入侵性之可能機轉...........................................................105
第六章 總結與展望............................................106
參考文獻.....................................................109
附錄...........................................................125

Agarwal B, Rao CV, Bhendwal S, Ramey WR, Shirin H, Reddy BS, Holt PR (1999) Lovastatin augments sulindac-induced apoptosis in colon cancer cells and potentiated chemopreventive effects of sulindac. Gastroenterology 117:838-847
Ain KB (1998) Anaplastic thyroid carcinoma: behavior, biology and therapeutic approaches. Thyroid. 8:715-726
Ain KB, Tofiq S, Taylor KD (1996) Antineoplastic activity of taxol against human anaplastic thyroid carcinoma cell lines in vitro and in vivo. J Clin Endocrinol Metab 81:3650-3653
Alberts AW, Chen J, Kuron G, Hunt V, Huff J, Hoffman C, Rothrock J, Lopez M, Joshua H, Harris E, Patchett A, Monaghan R, Currie S, Stapley E, Albers-Schonberg G, Hensens O, Hirshfield J, Hoogsteen K, Liesch J, Springer J (1980) Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent. Proc Natl Acad Sci U S A 77:3957-3961
Alonso DF, Farina HG, Skilton G, Gabri MR, De Lorenzo MS, Gomez DE (1998) Reduction of mouse mammary tumor formation and metastasis by lovastatin, an inhibitor of the mevalonate pathway of cholesterol synthesis. Breast Cancer Res Treat 50:83-93
Amano M, Chihara K, Kimura K, Fukata Y, Nakamura N, Matsuura Y, Kaibuchi K (1997) Formation of actin stress fibers and focal adhesions enhanced by Rho-kinase. Science 275:1308-1311
Anthony ML, Zhao M, Brindle KM (1999) Inhibition of phosphatidylcholine biosynthesis following induction of apoptosis in HL-60 cells. J Biol Chem 274:19686-19692
Banyard J, Anand-Apte B, Symons M, Zetter BR (2000) Motility and invasion are differentially modulated by Rho family GTPases. Oncogene 19:580-591
Bar-Sagi D, Feramisco JR (1985) Microinjection of the ras oncogene protein into PC12 cells induces morphological differentiation. Cell 42:841—848
Bergstrom JD, Westermark B, Heldin NE (2000) Epidermal growth factor receptor signaling activates met in human anaplastic thyroid carcinoma cells. Exp Cell Res 259:293-299
Bos JL (1989) Ras oncogenes in human cancer: a review. Cancer Res 49:4682-4689
Bouterfa HL, Sattelmeyer V, Czub S, Vordermark D, Roosen K, Tonn JC (2000) Inhibition of Ras farnesylation by lovastatin leads to downregulation of proliferation and migration in primary cultured human glioblastoma cells. Anticancer Res 20:2761-2771
Carragher NO, Levkau B, Ross R, Raines EW (1999) Degraded Collagen Fragments Promote Rapid Disassembly of Smooth Muscle Focal Adhesions That Correlates with Cleavage of pp125FAK, Paxillin, and Talin. J Cell Biol 147:619—629
Caruso MG, Notarnicola M, Santillo M, Cavallini A, Di Leo A (1999) Enhanced 3-hydroxy-3-methylglutaryl coenzyme A reductase in human colorectal cancer not expressing low density lipoprotein receptor. Anticancer Res 19:451-454
Casey PJ, Thissen JA, Moomaw JF (1991) Enzymatic modification of proteins with a geranylgeranyl isoprenoid. Proc Natl Acad Sci U S A 88:8631-8635
Chan AY, Bailly M, Zebda N, Segall JE, Condeelis JS (2000) Role of cofilin in epidermal growth factor-stimulated actin polymerization and lamellipod protrusion. J Cell Biol 148:531-542
Chang TC, Lai SM, Wen CY, Hsiao YL, Huang SH (2000) Three-dimensional cytomorphology and its relationship with clinical stage in fine needle aspiration biopsy of papillary thyroid carcinoma. Acta Cytol 44:633-639
Chen CJ, You SL, Lin LH, Hsu WL, Yang YW (2002) Cancer epidemiology and control in Taiwan: a brief review. Jpn J Clin Oncol 32:S66-S81
Chen Q, Lin TH, Der CJ, Juliano RL (1996) Integrin-mediated activation of MEK and mitogen-activated protein kinase is independent of Ras. J Biol Chem 271:18122—18127
Clark EA, Hynes RO (1996) Ras activation is necessary for integrin-mediated activation of extracellular signal-regulated kinase 2 and cytosolic phospholipase A2 but not for cytoskeletal organization. J Biol Chem 271:14814—14818
Clarke S (1992) Protein isoprenylation and methylation at carboxylterminal cysteine residues. Annu Rev Biochem 61:355—386
Colli S, Eligini S, Lalli M, Camera M, Paoletti R, Tremoli E (1997) Vastatins inhibit tissue factor in cultured human macrophages. A novel mechanism of protection against therothrombosis. Arterioscler Thromb Vasc Biol 17:265-272
Danesi R, McLellan CA, Myers CE (1995) Specific labeling of isoprenylated proteins: application to study inhibitors of the post-translational farnesylation and geranylgeranylation. Biochem Biophys Res Commun 206:637-643
Davigono J, Hanefeld M, Nakaya N, Hunninghake DB, Insull W, Ose L (1998) Clinical efficacy and safety of cerivastatin: summary of pivotal phase IIb/III studies. Atherosclerosis 139 (supp.1):S15-S22
DeGraba TJ (1997) Expression of inflammatory mediators and adhesion molecules in human atherosclerotic plaque. Neurology 49:S15-S19
Di Matola T, D'Ascoli F, Luongo C, Bifulco M, Rossi G, Fenzi G, Vitale M (2001) Lovastatin-induced apoptosis in thyroid cells: involvement of cytochrome c and lamin B. Eur J Endocrinol 145:645-650
Downward J (1998) Ras signalling and apoptosis. Curr Opin Genet Dev 8:49-54
Earnshaw WC, Martins LM, Kaufmann SH (1999) Mammalian caspases: structure, activation, substrates, and functions during apoptosis. Ann Rev Biochem 68:383-424
Fagin JA, Matsuo K, Karmakar A, Chen DL, Tang SH, Koeffler HP (1993) High prevalence of mutations of the p53 gene in poorly differentiated human thyroid carcinomas. J Clin Invest 91:179—184
Farina HG, Bublik DR, Alonso DF, Gomez DE (2002) Lovastatin alters cytoskeleton organization and inhibits experimental metastasis of mammary carcinoma cells. Clin Exp Metastasis 19:551-559
Farnsworth CC, Seabra MC, Ericsson LH, Gelb MH, Glomset JA (1994) Rab geranylgeranyl transferase catalyzes the geranylgeranylation of adjacent cysteines in the small GTPases Rab1A, Rab3A, and Rab5A. Proc Natl Acad Sci U S 91:11963-11967
Flinn HM, Ridley AJ (1996) Rho stimulates tyrosine phosphorylation of focal adhesion kinase, p130 and paxillin. J Cell Sci 109:1133-1141
Gille H, Downward J (1999) Multiple ras effector pathways contribute to G(1) cell cycle progression. J Biol Chem 274:22033—22040
Gilmore AP and Romer LH (1996) Inhibition of focal adhesion kinase (FAK) signaling in focal adhesions decreases cell motility and proliferation. Mol Biol Cell 7:1209—1224
Goldstein JL, Brown MS (1990) Regulation of the mevalonate pathway. Nature 343: 425-430
Gomez J, Martinez-A C, Gonzalez A, Rebollo A (1998) Dual role of Ras and Rho proteins: at the cutting edge of life and death. Immunol Cell Biol 76:125-134
Goretzki PE, Simon D, Frilling A, Witte J, Reiners C, Grussendorf M, Horster FA, Roher HD (1993) Surgical reintervention for differentiated thyroid carcinoma. Br J Surg 80:1009—1012
Guijarro C, Blanco-Colio LM, Ortego M, Alonso C, Ortiz A, Plaza JJ, Diaz C, Hernandez G, Egido J (1998) 3-Hydroxy-3-methylglutaryl coenzyme a reductase and isoprenylation inhibitors induce apoptosis of vascular smooth muscle cells in culture. Circ Res 83:490-500
Hampton RY, Rine J (1994) Regulated degradation of HMG-CoA reductase, an integral membrane protein of the endoplasmic reticulum, in yeast. J Cell Biol 125:299—312
Hanks SK, Ryzhova L, Shin NY, Brabek J (2003) Focal adhesion kinase signaling activities and their implications in the control of cell survival and motility. Front Biosci 8:D982-D996
Hill CS, Wynne J, Treisman R (1995) The Rho family GTPases RhoA, Rac1, and CDC42Hs regulate transcriptional activation by SRF. Cell 81:1159—1170
Hippenstiel S, Schmeck B, N'Guessan PD, Seybold J, Krull M, Preissner K, Eichel-Streiber CV, Suttorp N (2002) Rho protein inactivation induced apoptosis of cultured human endothelial cells. Am J Physiol Lung Cell Mol Physiol 283:L830-L838
Hirohashi S (1998) Inactivation of the E-cadherin-mediated cell adhesion system in human cancers. Am J Pathol 153:333-339
Ho KY, Tsai CC, Chen CP, Huang JS, Lin CC (2001) Antimicrobial activity of honokiol and magnolol isolated from Magnolia officinalis. Phytother Res 15:139-141
Hood JD, Cheresh DA (2002) Role of integrins in cell invasion and migration. Nat Rev Cancer 2:91-100
Howe AK, Juliano RL (1998) Distinct mechanisms mediate the initial and sustained phases of integrin-mediated activation of the Raf/MEK/ mitogen-activated protein kinase cascade. J Biol Chem 273:27268—27274
Ilic D, Furuta Y, Kanazawa S, Takeda N, Sobue K, Nakatsuji N, Nomura S, Fujimoto J, Okada M, Yamamoto T (1995) Reduced cell motility and enhanced focal adhesion contact formation in cells from FAK-deficient mice. Nature 377:539-544
Ishizaki T, Naito M, Fujisawa K, Maekawa M, Watanabe N, Saito Y, Narumiya S (1997) p160ROCK, a Rho-associated coiled-coil forming protein kinase, works downstream of Rho and induces focal adhesions. FEBS Lett 404:118-124
Jaffe AB, Hall A (2002) Rho GTPases in transformation and metastasis. Adv Cancer Res 84:57-80
Johnnessen JV, Sobrinho-Simoes M (1982) Follicular carcinoma of the human thyroid gland: An ultrastructural study with emphasis on scanning electron microscopy. Diag Histopathol 5:113—127
Kawata S, Takaishi K, Nagase T, Ito N, Matsuda Y, Tamura S, Matsuzawa Y, Tarui S (1990) Increase in the active form of 3-hydroxy-3-methylglutaryl-coenzyme A reductase in human hepatocellular carcinoma: possible mechanism for alteration of cholesterol biosynthesis. Cancer Res 50:3270-3273
Kerr JF, Wyllie AH, Currie AR (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26:239-257
Kim JH, Leeper RD (1983) Treatment of anaplastic giant and spindle cell carcinoma of the thyroid gland with combination Adriamycin and radiation therapy. A new approach. Cancer 52:954-957
Kim WS, Kim MM, Choi HJ, Yoon SS, Lee MH, Park K, Park CH, Kang WK (2001) Phase II study of high-dose lovastatin in patients with advanced gastric adenocarcinoma. Invest New Drugs 19:81—83
Kimura K, Ito M, Amano M, Chihara K, Fukata Y, Nakafuku M, Yamamori B, Feng J, Nakano T, Okawa K, Iwamatsu A, Kaibuchi K (1996) Regulation of myosin phosphatase by Rho and Rho-associated kinase. Science 273:245-248
Kornberg L, Earp HS, Parsons JT, Schaller M, Juliano RL (1992) Cell adhesion or integrin clustering increases phosphorylation of a focal adhesion-associated tyrosine kinase. J Biol Chem 267:23439-23442
Kusama T, Mukai M, Iwasaki T, Tatsuta M, Matsumoto Y, Akedo H, Nakamura H (2001) Inhibition of epidermal growth factor-induced RhoA translocation and invasion of human pancreatic cancer cells by 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. Cancer Res 61:4885-4891
Lerner EC, Zhang TT, Knowles DB, Qian Y, Hamilton AD, Sebti SM (1997) Inhibition of the prenylation of K-Ras, but not H- or N-Ras, is highly resistant to CAAX peptidomimetics and requires both a farnesyltransferase and a geranylgeranyltransferase I inhibitor in human tumor cell lines. Oncogene 15: 1283-1288
Leung T, Chen XQ, Manser E, Lim L (1996) The p160 Rho-binding kinase ROK is a member of a kinase family and is involved in the reorganization of the cytoskeleton. Mol Cell Biol 16:5313-5327
Li X, Liu L, Tupper JC, Bannerman DD, Winn RK, Sebti SM, Hamilton AD, Harlan JM (2002) Inhibition of protein geranylgeranylation and RhoA/RhoA kinase pathway induces apoptosis in human endothelial cells. J Biol Chem 277:15309-15316
Liu B, Itoh H, Louie O, Kubota K, Kent KC (2002) The signaling protein Rho is necessary for vascular smooth muscle migration and survival but not for proliferation. Surgery 132:317-325
Macaluso M, Russo G, Cinti C, Bazan V, Gebbia N, Russo A (2002) Ras family genes: an interesting link between cell cycle and cancer. J Cell Physiol 192:125-130
Macaulay RJ, Wang W, Dimitroulakos J, Becker LE, Yeger H (1999) Lovastatin-induced apoptosis of human medulloblastoma cell lines in vitro. J Neurooncol 42:1-11
Maeda T, Matsunuma A, Kawane T, Horiuchi N (2001) Simastatin promotes osteoblast differentiation and mineralization in MC3T3-E1 cells. Biochem Biophys Res Commun 280:874—877
Majno G, Joris I (1995) Apoptosis, oncosis, and necrosis. An overview of cell death. Am J Pathol 146:3-15
Marshall CJ (1995) Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 80:179—185
Marx J (2002) Nobel Prize in Physiology or Medicine. Tiny worm takes a star turn. Science 298:526
Massy ZA, Keane WF, Kasiske BL (1996) Inhibition of the mevalonate pathway: benefits beyond cholesterol reduction? Lancet 347:102—103
Matar P, Rozados VR, Binda MM, Roggero EA, Bonfil RD, Scharovsky OG (1999) Inhibitory effect of lovastatin on spontaneous metastasis derived from a rat lymphoma. Clin Exp Metastasis 17:19-25
Mazzaferri EL, Jhiang SM (1994) Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med 97:418-428
Mehta N, Hordies J, Sykes D, Doerr RJ, Cohen SA (1998) Low density lipoproteins and lovastatin modulate the organ-specific transendothelial migration of primary and metastatic human colon adenocarcinoma cell lines in vitro. Clin Exp Metastasis 16:587-594
Mignotte B, Vayssiere JL (1998) Mitochondria and apoptosis. Eur J Biochem 252: 1-15
Miquel K, Pradines A, Sun J, Qian Y, Hamilton AD, Sebti SM, Favre G (1997) GGTI-298 induces G0-G1 block and apoptosis whereas FTI-277 causes G2-M enrichment in A549 cells. Cancer Res 57:1846-1850
Miquel K, Pradines A, Terce F, Selmi S, Favre G (1998) Competitive inhibition of choline phosphotransferase by geranylgeraniol and farnesol inhibits phosphatidylcholine synthesis and induces apoptosis in human lung adenocarcinoma A549 cells. J Biol Chem 273:26179-26186
Murga C, Zohar M, Teramoto H, Gutkind JS (2002) Rac1 and RhoG promote cell survival by the activation of PI3K and Akt, independently of their ability to stimulate JNK and NF-kappaB. Oncogene 21:207-216
Nagata S (1997) Apoptosis by death factor. Cell 88:355-365
Nakanishi M, Goldstein JL, Brown MS (1988) Multivalent control of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Mevalonate-derived product inhibits translation of mRNA and accelerates degradation of enzyme. J Biol Chem 263:8929-8937
Ne´gre-Aminou P, van Vliet AK, van Erick M, van Thiel CF, van Leeuwen REW, Cohen LH (1997) Inhibition of proliferation of human smooth muscle cells by various HMG-CoA reductase inhibitors; comparison with other human cell types. Biochim Biophys Acta 1345:259-268
Nesland JM, Sobrinho-Simoes M, Johnnessen JV (1987) Scanning electron microscopy of the human thyroid gland and its disorders. Scann Microsc 1:1797-1810
Niederle B, Roka R, Schemper M, Fritsch A, Weissel M, Ramach W (1986) Surgical treatment of distant metastases in differentiated thyroid cancer: indication and results. Surgery 100:1088-1097
Nishida K, Kaziro Y, Satoh T (1999) Anti-apoptotic function of Rac in hematopoietic cells. Oncogene 18:407-415
Nobes CD, Hall A (1999) Rho GTPases control polarity, protrusion, and adhesion during cell movement. J Cell Biol 144:1235-1244
Nunez G, Benedict MA, Hu Y, Inohara N (1998) Caspases: the proteases of the apoptotic pathway. Oncogene 17:3237-3245
Oktay M, Wary KK, Dans M, Birge RB, Giancotti FG (1999) Integrin-mediated activation of focal adhesion kinase is required for signaling to Jun NH2- terminal kinase and progression through the G1 phase of the cell cycle. J Cell Biol 145:1461-1469
Olson MF, Paterson HF, Marshall CJ (1998) Signals from Ras and Rho GTPases interact to regulate expression of p21Waf1/Cip1. Nature 394:295-299
Osterop AP, Medema RH, vd Zon GC, Bos JL, Moller W, Maassen JA (1993) Epidermal growth factor receptors generate Ras GTP more efficiently than insulin receptors. Eur J Biochem 212:477-482
Owen JD, Ruest PJ, Fry DW, Hanks SK (1999) Induced focal adhesion kinase (FAK) expression in FAK-null cells enhances cell spreading and migration requiring both auto- and activation loop phosphorylation sites and inhibits adhesion-dependent tyrosine phosphorylation of Pyk2. Mol Cell Biol 19:4806-4818
Pan J, Xu G, Yeung SC (2000) Cytochrome c release is upstream to activation of caspase-9, caspase-8, and caspase-3 in the enhanced apoptosis of anaplastic thyroid cancer cells induced by manumycin and paclitaxel. J Clin Endocrinol Metab 86:4731-4740
Panetti TS (2002) Related Tyrosine phosphorylation of paxillin, FAK, and p130CAS: effects on cell spreading and migration. Front Biosci 7:d143-d150
Parhami F, Mody N, Gharavi N, Ballard AJ, Tintut Y, Demer LL (2002) Role of the cholesterol biosynthetic pathway in osteoblastic differentiation of marrow stromal cells. J Bone Miner Res 17:1997-2003
Parsons JT, Martin KH, Slack JK, Taylor JM, Weed SA (2000) Focal adhesion kinase: a regulator of focal adhesion dynamics and cell movement. Oncogene 19:5606-5613
Pirillo A, Jacoviello C, Longoni C, Radaelli A, Catapano AL (1997) Simvastatin modulates the heat shock response and cytotoxicity mediated by oxidized LDL in cultured human endothelial smooth muscle cells. Biochem Biophys Res Commun 231:437-441
Plosker GL, Wagstaff AJ (1996) Fluvastatin: a review of its pharmacology and used in the management of hypercholesterolemia. Drug 51:433-459
Qiu RG, Chen J, McCormick F, Symons M (1995) A role for Rho in Ras transformation. Proc Natl Acad Sci U S A 92:11781-11785
Raff MC (1992) Social controls on cell survival and cell death. Nature 356:397-400
Riento K, Ridley AJ (2003) ROCKs: multifunctional kinases in cell behaviour. Nat Rev Mol Cell Biol 4:446-456
Rul W, Zugasti O, Roux P, Peyssonnaux C, Eychene A, Franke TF, Lenormand P, Fort P, Hibner U (2002) Activation of ERK, controlled by Rac1 and Cdc42 via Akt, is required for anoikis. Ann N Y Acad Sci 973:145-8
Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Cole TG, Brown L, Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald E (1996) The effect of pravastatin on coronary events after myocardial infraction in patients with average cholesterol levels. New Engl J Med 335:1001-1009
Schlaepfer DD, Hanks SK, Hunter T, van der Geer P (1994) Integrin-mediated signal transduction inked to Ras pathway by GRB2 binding to focal adhesion kinase. Nature 372:786-791
Schmutzler C, Brtko J, Bienert K, Kohrle J (1996) Effects of retinoids and role of retinoic acid receptors in human thyroid carcinomas and cell lines derived therefrom. Exp Clin Endocrinol Diabetes 104(Suppl 4):16-19
Schmutzler C, Kohrle J (2000) Retinoic acid redifferentiation therapy for thyroid cancer. Thyroid 10:393—406
Seabra MC, Goldstein JL, Sudhof TC, Brown MS (1992) Rab geranylgeranyl transferase. A multisubunit enzyme that prenylates GTP-binding proteins terminating in Cys-X-Cys or Cys-Cys. J Biol Chem 267:14497-1503
Sears RC, Nevins JR (2002) Signaling networks that link cell proliferation and cell fate. J Biol Chem 277:11617-11620
Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW (1995) Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of cotland Coronary Prevention Study Group. New Engl J Med 333:1301-1307
Sherman SI (2003) Thyroid carcinoma. Lancet 361:501-511
Shimaoka K, Schoenfeld DA, DeWys WD, Creech RH, DeConti R (1985) A randomized trial of doxorubicin versus doxorubicin plus cisplatin in patients with advanced thyroid carcinoma. Cancer 56:2155-2160
Siegel-Axel DI (2003) Cerivastatin: a cellular and molecular drug for the future? Cell Mol Life Sci 60:144-164
Simon D, Koehrle J, Reiner C, Boerner AR, Schmutzler C, Mainz K, Goretzki PE, Roeher HD (1988) Redifferentiation therapy with retinoids: therapeutic option for advanced follicular and papillary thyroid carcinoma. World J Surg 22:569-574
Simon D, Kohrle J, Schmutzler C, Mainz K, Reiners C, Roher HD (1996) Redifferentiation therapy of differentiated thyroid carcinoma with retinoic acid: basics and first clinical results. Exp Clin Endocrinol Diabetes 104(Suppl 4):13-15
Sindermann JR, Fan L, Weigel KA, Troyer D, Muller JG, Schmidt A, March KL, reithardt G (2000) Differences in the effects of HMG-CoA reductase inhibitors on proliferation and viability of smooth muscle cells in culture. Atherosclerosis 150:331-341
Spencer ML, Shao H, Andres DA (2002) Induction of neurite extension and survival in pheochromocytoma cells by the Rit GTPase. J Biol Chem 277:20160-20168
Stupack DG, Cheresh DA (2002) Get a ligand, get a life: integrins, signaling and cell survival. J Cell Sci 115:3729-3738
Tan RK, Finley RK, III, Driscoll D, Bakamjian V, Hicks WL, Jr., Shedd DP (1995) Anaplastic carcinoma of the thyroid: a 24-year experience. Head Neck 17: 41-48
Tennvall J, Lundell G, Hallquist A, Wahlberg P, Wallin G, Tibblin S (1994) Combined doxorubicin, hyperfractionated radiotherapy, and surgery in anaplastic thyroid carcinoma: report on two protocols. The Swedish Anaplastic Thyroid Cancer Group. Cancer 74:1348-1354
Thibault A, Samid D, Tompkins AC, Figg WD, Cooper MR, Hohl RJ, Trepel J, Liang B, Patronas N, Venzon DJ, Reed E, Myers CE (1996) Phase I study of lovastatin, an inhibitor of the mevalonate pathway, in patients with cancer. Clin Cancer Res 2:483—491
Totsukawa G, Yamakita Y, Yamashiro S, Hartshorne DJ, Sasaki Y, Matsumura F (2000) Distinct roles of ROCK (Rho-kinase) and MLCK in spatial regulation of MLC phosphorylation for assembly of stress fibers and focal adhesions in 3T3 fibroblasts. J Cell Biol 150:797-806
Trahey M, McCormick F (1997) A cytoplasmic protein stimulates normal N-ras p21 GTPase, but does not affect oncogenic mutants. Science 238:542-545
Trosko JE, Ruch RJ (1998) Cell-cell communication in carcinogenesis. Front Biosci 3:D208-236
Tubiana M, Haddad E, Schlumberger M, Hill C, Rougier P, Sarrazin D (1985) External radiotherapy in thyroid cancers. Cancer 55:2062-2071
Van De Donk NW, Kamphuis MM, Lokhorst HM, Bloem AC (2002) The cholesterol lowering drug lovastatin induces cell death in myeloma plasma cells. Leukemia 16:1362-1371
Vaughan CJ, Murphy MB, Buckley BM (1996) Statins do more than just lower cholesterol. Lancet 348:1079-1082
Venkatesh YS, Ordonez NG, Schultz PN, Hickey RC, Goepfert H, Samaan NA (1990) Anaplastic carcinoma of the thyroid: a clinical pathologic study of 121 cases. Cancer 66:321-330
Vitale M, Di Matola T, Rossi G, Laezza C, Fenzi G, Bifulco M (1999) Prenyltransferase inhibitors induce apoptosis in proliferating thyroid cells through a p53-independent CrmA-sensitive, and caspase-3-like protease-dependent mechanism. Endocrinology 140:698-704
Wachtershauser A, Akoglu B, Stein J (2001) HMG-CoA reductase inhibitor mevastatin enhances the growth inhibitory effect of butyrate in the colorectal carcinoma cell line Caco-2. Carcinogenesis 22:1061-1067
Wang CY, Zhong WB, Chang TC, Lai SM, Tsai YF (2003) Lovastatin, a HMG Co-A reductase inhibitor, induces apoptosis and differentiation in human anaplastic thyroid carcinoma cells. J Clin Endocrinol Metab 88:3021-3026
Wang CY, Zhong WB, Chang TC, Lai SM, Tsai YF (2002) Tumor necrosis factor alpha induces three-dimensional cytomorphologic differentiation of human anaplastic thyroid carcinoma cells through activation of nuclear factor kappaB. Cancer 95:1827-1833
Wang TH, Wang HS (1999) Apoptosis: Overview and clinical significance. J Formos Med Assoc 98:381-393
Weber C, Erl W, Weber PC (1995) Lovastatin induces differentiation of Mono Mac 6 cells. Cell Biochem Funct 13:273—277
White MA, Nicolette C, Minden A, Polverino A, Van Aelst L, Karin M, Wigler MH (1995) Multiple Ras functions can contribute to mammalian cell transformation. Cell 80:533-541
White MA, Vale T, Camonis JH, Schaefer E, Wigler MH (1996) A role for the Ral guanine nucleotide dissociation stimulator in mediating Ras-induced transformation. J Biol Chem 271:16439-16442
Williams SD, Birch R, Einhorn LH (1986) Phase II evaluation of doxorubicin plus cisplatin in advanced thyroid cancer: a Southeastern Cancer Study Group Trial. Cancer Treat Rep 70:405-407
Xia Z, Tan MM, Wong WW, Dimitroulakos J, Minden MD, Penn LZ (2001) Blocking protein geranylgeranylation is essential for lovastatin-induced apoptosis of human acute myeloid leukemia cells. Leukemia 15:1398-407
Yamamoto M, Marui N, Sakai T, Morii N, Kozaki S, Ikai K, Imamura S, Narumiya S (1993) ADP-ribosylation of the rhoA gene product by botulinum C3 exoenzyme causes Swiss 3T3 cells to accumulate in the G1 phase of the cell cycle. Oncogene 8:1449-1455
Yasunari K, Maeda K, Minami M, Yoshikawa J (2001) HMG-CoA reductase inhibitors prevent migration of human coronary smooth muscle cells through suppression of increase in oxidative stress. Arterioscler Thromb Vasc Biol 21:937-942
Yoshioka K, Matsumura F, Akedo H, Itoh K (1998) Small GTP-binding protein Rho stimulates the actomyosin system, leading to invasion of tumor cells. J Biol Chem 273:5146-5154
Zhang FL, Casey PJ (1996) Protein prenylation: molecular mechanisms and functional consequences. Annu Rev Biochem 65:241-269
Zhong WB, Wang CY, Chang TC, Lee WS (2003) Lovastatin induces apoptosis of anaplastic thyroid cancer cells via inhibition of protein geranylgeranylation and de novo protein synthesis. Endocrinology 144:3852-3859

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