Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/23583
標題: 環格列酮在多型惡性神經膠細胞瘤抑制腫瘤細胞生長之探討
The Role of Ciglitazone Inhibits Tumor Growth in Human Glioblastoma Multiforme
作者: 胡懷云
Hu, Huai-Yun
關鍵字: Gioblastoma multiforme;多形惡性神經膠質瘤;PPARγ agonists;proteasome;lysosome;anti-cancer drugs;PPARγ活化劑;蛋白酶體;溶酶體;抗癌藥物
出版社: 生命科學系所
引用: Adams J (2004). The proteasome: A suitable antineoplastic target. Nature Reviews Cancer 4, 349-360. Akasaki Y, Liu G, Matundan HH, Ng H, Yuan X, Zeng Z, Black KL, and Yu JS (2006). A peroxisome proliferator-activated receptor-γ agonist, troglitazone, facilitates caspase-8 and -9 activities by increasing the enzymatic activity of protein-tyrosine phosphatase-1b on human glioma cells. Journal of Biological Chemistry 281, 6165-6174. Birner P, Toumangelova-Uzeir K, Natchev S, and Guentchev M (2010). Stat3 tyrosine phosphorylation influences survival in glioblastoma. Journal of Neuro-Oncology 100, 339-343. Brantley EC, and Benveniste EN (2008). Signal transducer and activator of transcription-3: A molecular hub for signaling pathways in gliomas. Molecular Cancer Research 6, 675-684. Bromberg J, and Darnell JE (2000). The role of stats in transcriptional control and their impact on cellular function. Oncogene 19, 2468-2473. Bromberg JF, Horvath CM, Besser D, Lathem WW, and Darnell JE (1998). Stat3 activation is required for cellular transformation by v-src. Molecular and Cellular Biology 18, 2553-2558. Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C, and Darnell Jr JE (1999). Stat3 as an oncogene. Cell 98, 295-303. Calò V, Migliavacca M, Bazan V, Macaluso M, Buscemi M, Gebbia N, and Russo A (2003). Stat proteins: From normal control of cellular events to tumorigenesis. Journal of Cellular Physiology 197, 157-168. Catlett-Falcone R, Landowski TH, Oshiro MM, Turkson J, Levitzki A, Savino R, Ciliberto G, Moscinski L, Fernández-Luna JL, Nuñez G, Dalton WS, and Jove R (1999). Constitutive activation of stat3 signaling confers resistance to apoptosis in human u266 myeloma cells. Immunity 10, 105-115. Chattopadhyay N, Singh DP, Heese O, Godbole MM, Sinohara T, Black PM, and Brown EM (2000). Expression of peroxisome proliferator-activated receptors (PPARs) in human astrocytic cells: PPARγ agonists as inducers of apoptosis. Journal of Neuroscience Research 61, 67-74. Chondrogianni N, Fragoulis E, and Gonos E (2002). Protein degradation during aging: The lysosome-, the calpain- and the proteasome-dependent cellular proteolytic systems. Biogerontology 3, 121-123. Dasgupta A, Raychaudhuri B, Haqqi T, Prayson R, Van Meir EG, Vogelbaum M, and Haque SJ (2009). Stat3 activation is required for the growth of u87 cell-derived tumours in mice. European Journal of Cancer 45, 677-684. Epling-Burnette PK, Liu JH, Catlett-Falcone R, Turkson J, Oshiro M, Kothapalli R, Li Y, Wang JM, Yang-Yen HF, Karras J, Jove R, and Loughran TP (2001). Inhibition of stat3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased mcl-1 expression. The Journal of Clinical Investigation 107, 351-362. Faich GA, and Moseley RH (2001). Troglitazone (rezulin) and hepatic injury. Pharmacoepidemiology and Drug Safety 10, 537-547. Furnari FB, Fenton T, Bachoo RM, Mukasa A, Stommel JM, Stegh A, Hahn WC, Ligon KL, Louis DN, Brennan C, Chin L, DePinho RA, and Cavenee WK (2007). Malignant astrocytic glioma: Genetics, biology, and paths to treatment. Genes & Development 21, 2683-2710. Grommes C, Landreth GE, and Heneka MT (2004). Antineoplastic effects of peroxisome proliferatoractivated receptor γ agonists. The Lancet Oncology 5, 419-429. Henson JW, Schnitker BL, Correa KM, von Deimling A, Fassbender F, Xu H-J, Benedict WF, Yandell DW, and Louis DN (1994). The retinoblastoma gene is involved in malignant progression of astrocytomas. Annals of Neurology 36, 714-721. Irie-Sasaki J, Sasaki T, Matsumoto W, Opavsky A, Cheng M, Welstead G, Griffiths E, Krawczyk C, Richardson CD, Aitken K, Iscove N, Koretzky G, Johnson P, Liu P, Rothstein DM, and Penninger JM (2001). Cd45 is a jak phosphatase and negatively regulates cytokine receptor signalling. Nature 409, 349-354. Issemann I, and Green S (1990). Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature 347, 645-650. Klingmüller U, Lorenz U, Cantley LC, Neel BG, and Lodish HF (1995). Specific recruitment of sh-ptp1 to the erythropoietin receptor causes inactivation of jak2 and termination of proliferative signals. Cell 80, 729-738. Krex D, Klink B, Hartmann C, von Deimling A, Pietsch T, Simon M, Sabel M, Steinbach JP, Heese O, Reifenberger G, Weller M, Schackert G, and Network ftGG (2007). Long-term survival with glioblastoma multiforme. Brain 130, 2596-2606. Lai E, Teodoro T, and Volchuk A (2007). Endoplasmic reticulum stress: Signaling the unfolded protein response. Physiology 22, 193-201. Li MY, Lee TW, Yim AP, and Chen GG (2006). Function of PPARγ and its ligands in lung cancer. Critical Reviews in Clinical Laboratory Sciences 43, 183-202. Michalik L, Desvergne B, and Wahli W (2004). Peroxisome-proliferator-activated receptors and cancers: Complex stories. Nature Reviews Cancer 4, 61-70. Nam DH, Ramachandran S, Song DK, Kwon KY, Jeon DS, Shin SJ, Kwon SH, Cha SD, Bae I, and Cho CH (2007). Growth inhibition and apoptosis induced in human leiomyoma cells by treatment with the PPAR gamma ligand ciglitizone. Molecular Human Reproduction 13, 829-836. Ng SS, Li Y, Cheung WKC, Kung H-F, and Lin MC (2011). Glioblastoma multiforme: Role of cell cycle-related kinase protein (method) tumors of the central nervous system, volume 1. In, Hayat M A, ed. (Springer Netherlands), pp. 167-171. Niu G, Wright KL, Huang M, Song L, Haura E, Turkson J, Zhang S, Wang T, Sinibaldi D, Coppola D, Heller R, Ellis LM, Karras J, Bromberg J, Pardoll D, Jove R, and Yu H (2002). Constitutive stat3 activity up-regulates vegf expression and tumor angiogenesis. Oncogene 21, 2000-2008. Panigrahy D, Singer S, Shen LQ, Butterfield CE, Freedman DA, Chen EJ, Moses MA, Kilroy S, Duensing S, Fletcher C, Fletcher JA, Hlatky L, Hahnfeldt P, Folkman J, and Kaipainen A (2002). PPARγ ligands inhibit primary tumor growth and metastasis by inhibiting angiogenesis. The Journal of Clinical Investigation 110, 923-932. Qin C, Burghardt R, Smith R, Wormke M, Stewart J, and Safe S (2003). Peroxisome proliferator-activated receptor γ agonists induce proteasome-dependent degradation of cyclin d1 and estrogen receptor α in MCF-7 breast cancer cells. Cancer Research 63, 958-964. Rahaman SO, Harbor PC, Chernova O, Barnett GH, Vogelbaum MA, and Haque SJ (2002). Inhibition of constitutively active stat3 suppresses proliferation and induces apoptosis in glioblastoma multiforme cells. Oncogene 21, 8404-8413. Schwartz GK, and Shah MA (2005). Targeting the cell cycle: A new approach to cancer therapy. Journal of Clinical Oncology 23, 9408-9421. Servidei T, Aoki Y, Lewis SE, Symes A, Fink JS, and Reeves SA (1998). Coordinate regulation of stat signaling and c-fosexpression by the tyrosine phosphatase shp-2. Journal of Biological Chemistry 273, 6233-6241. Sheu WH-H, Ou H-C, Chou F-P, Lin T-M, and Yang C-H (2006). Rosiglitazone inhibits endothelial proliferation and angiogenesis. Life Sciences 78, 1520-1528. Shin SW, Seo CY, Han H, Han JY, Jeong JS, Kwak JY, and Park JI (2009). 15d-PGJ2 induces apoptosis by reactive oxygen species-mediated inactivation of akt in leukemia and colorectal cancer cells and shows in vivo antitumor activity. Clinical Cancer Research 15, 5414-5425. Sidransky D, Mikkelsen T, Schwechheimer K, Rosenblum ML, Cavanee W, and Vogelstein B (1992). Clonal expansion of p53 mutant cells is associated with brain tumour progression. Nature 355, 846-847. Singletary K, and Milner J (2008). Diet, autophagy, and cancer: A review. Cancer Epidemiology Biomarkers & Prevention 17, 1596-1610. Strakova N, Ehrmann J, Dzubak P, Bouchal J, and Kolar Z (2004). The synthetic ligand of peroxisome proliferator-activated receptor-γ ciglitazone affects human glioblastoma cell lines. Journal of Pharmacology and Experimental Therapeutics 309, 1239-1247. Toyoda M, Takagi H, Horiguchi N, Kakizaki S, Sato K, Takayama H, and Mori M (2002). A ligand for peroxisome proliferator activated receptor γ inhibits cell growth and induces apoptosis in human liver cancer cells. Gut 50, 563-567. Wei L-H, Kuo M-L, Chen C-A, Chou C-H, Lai K-B, Lee C-N, and Hsieh C-Y (2003). Interleukin-6 promotes cervical tumor growth by vegf-dependent angiogenesis via a stat3 pathway. Oncogene 22, 1517-1527. Wen PY, and Kesari S (2008). Malignant gliomas in adults. New England Journal of Medicine 359, 492-507. Yahata Y, Shirakata Y, Tokumaru S, Yamasaki K, Sayama K, Hanakawa Y, Detmar M, and Hashimoto K (2003). Nuclear translocation of phosphorylated stat3 is essential for vascular endothelial growth factor-induced human dermal microvascular endothelial cell migration and tube formation. Journal of Biological Chemistry 278, 40026-40031. Yang F-g, Zhang Z-w, Xin D-q, Shi C-j, Wu J-p, Guo Y-l, and Guan Y-f (2005). Peroxisome proliferator-activated receptor γ ligands induce cell cycle arrest and apoptosis in human renal carcinoma cell lines1. Acta Pharmacologica Sinica 26, 753-761. Yu C, Meyer D, Campbell G, Larner A, Carter-Su C, Schwartz J, and Jove R (1995). Enhanced DNA-binding activity of a stat3-related protein in cells transformed by the src oncoprotein. Science 269, 81-83. Yu H, and Jove R (2004). The stats of cancer - new molecular targets come of age. Nature Reviews Cancer 4, 97-105. Zander T, Kraus JA, Grommes C, Schlegel U, Feinstein D, Klockgether T, Landreth G, Koenigsknecht J, and Heneka MT (2002). Induction of apoptosis in human and rat glioma by agonists of the nuclear receptor PPARγ. Journal of Neurochemistry 81, 1052-1060. Zhang W, Zhang H, and Xing L (2006). Influence of ciglitazone on A549 cells growth in vitro and in vivo and mechanism. Journal of Huazhong University of Science and Technology [Medical Sciences] 26, 36-39.
摘要: 
多型惡性神經膠細胞瘤(glioblastoma multiforme, GBM)是大腦最常見的惡性腫瘤,生長快速也具侵襲性,治療方法多為手術、放射性以及化學治療。給予手術後放射性再加上化療,中期存活將延長至一年,但是五年存活率仍是非常的低。PPAR活化劑thiazolidinediones為臨床使用治療第二型糖尿病的藥物,已有文獻指出其抗腫瘤生長的效果,但其作用機制尚未完全釐清,因此本實驗使用PPARγ活化劑來檢測其對GBM抑制生長的功用。在體外試驗中,首先在軟瓊膠生長實驗中顯示PPARγ活化劑會抑制GBM細胞生長,接著利用西方墨點法檢測與腫瘤生長和血管新生相關的蛋白質STAT3,PPARγ活化劑會抑制STAT3於tyrosine 705位點的磷酸化。抑制STAT3磷酸化,主要是透過誘導SHP-2蛋白質增加及活性增加,並以免疫沉澱法及免疫螢光染色觀察SHP-2與STAT3的交互作用。PPARγ活化劑也會抑制細胞週期相關蛋白質Cyclin D1、Cyclin E、CDK2及CDK4的表現,同時會活化蛋白酶體(proteasome)及溶酶體(lysosome)來降解細胞週期相關蛋白質。另外,本實驗中PPARγ活化劑會誘導自噬(autophagy)標記LC3表現量增加及acidic vesicular oranganelles(AVOs)產生。傷口癒合試驗及酶譜分析顯示PPARγ活化劑會抑制GBM細胞移動活性及MMP2與MMP9的活性。此外,在動物體內試驗中顯示,PPARγ活化劑會抑制皮下腫瘤生長與血管新生。本研究顯示,PPARγ活化劑可以有效的抑制GBM腫瘤生長,可成為具有開發潛力的GBM抗癌藥物。

Gioblastoma multiforme (GBM) is the most common and most aggressive malignant tumor in brain. The three most common patient's treatments for GBM include surgery, radiation therapy, and chemotherapy. The survival can be prolong from a range of 3 to 4 months to a range of 7 to 12 months when combine the treatment surgery, radiation therapy, and chemotherapy. But GBM is still one of the worst 5-year survival rates among all human cancers. PPARγ agonists are used widely in patients with type 2 diabetes mellitus. Previous studies showed that the potent anticancer effects of PPARγ agonists but the mechanisms are not well understood. This study examed the anticancer effects on GBM. We showed that the inhibitory effect of PPARγ agonists on tumor cells in soft agar assay. Our experiments demonstrated that ciglitazone induced SHP-2 protein expression and dephosphorylation of STAT3 at tyrosine 705 then by using immunoprecipitation and immunofluorescence stain to exam the interaction and co-localization of SHP-2 and phospho-STAT3 (Tyr705). In addition, ciglitazone decreased the protein expression of Cyclin D1, Cyclin E, CDK2, and CDK4 by activated proteasome and lysosome to degrade cell cycle related protein. Ciglitazone also induced autophagy marker LC3 expression and acidic vesicular organelles (AVOs) in this study. We used wound healing assay and zymography to test the inhibitory effects of ciglitazone, the results showed ciglitazone inhibited cell mobility and activity of MMP2 and MMP9. In animal experiment, PPARγ agonists suppressed tumor growth and angiogenesis. The overall findings indicated that PPARγ agonists could be a promising drug candidate in treat gioblastoma multiforme.
URI: http://hdl.handle.net/11455/23583
其他識別: U0005-0202201223404800
Appears in Collections:生命科學系所

Show full item record
 
TAIR Related Article

Google ScholarTM

Check


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.