Please use this identifier to cite or link to this item:
標題: Cdk5蛋白於膀胱癌及前列腺癌中扮演角色之探討
Investigation of the roles of Cdk5 protein in bladder cancer and prostate cancer
作者: Eugene Lin
關鍵字: Cdk5;p35;膀胱癌;前列腺癌;Cdk5;p35;bladder cancer;prostate cancer
引用: Avizienyte, E., and Frame, M. C. (2005). Src and FAK signalling controls adhesion fate and the epithelial-to-mesenchymal transition. Current opinion in cell biology 17, 542-547. Berx, G., Cleton-Jansen, A. M., Nollet, F., de Leeuw, W. J., van de Vijver, M., Cornelisse, C., and van Roy, F. (1995). E-cadherin is a tumour/invasion suppressor gene mutated in human lobular breast cancers. The EMBO journal 14, 6107-6115. Brausi, M., Witjes, J. A., Lamm, D., Persad, R., Palou, J., Colombel, M., Buckley, R., Soloway, M., Akaza, H., and Bohle, A. (2011). A Review of Current Guidelines and Best Practice Recommendations for the Management of Nonmuscle Invasive Bladder Cancer by the International Bladder Cancer Group. J Urol. Chen, M. C., Huang, C. Y., Hsu, S. L., Lin, E., Ku, C. T., Lin, H., and Chen, C. M. (2012). Retinoic Acid Induces Apoptosis of Prostate Cancer DU145 Cells through Cdk5 Overactivation. Evid Based Complement Alternat Med 2012, 580736. Choi, H. S., Lee, Y., Park, K. H., Sung, J. S., Lee, J. E., Shin, E. S., Ryu, J. S., and Kim, Y. H. (2009). Single-nucleotide polymorphisms in the promoter of the CDK5 gene and lung cancer risk in a Korean population. J Hum Genet 54, 298-303. Daneshmand, S. (2013). Determining the role of cystectomy for high-grade T1 urothelial carcinoma. Urol Clin North Am 40, 233-247. Dhavan, R., and Tsai, L. H. (2001). A decade of CDK5. Nat Rev Mol Cell Biol 2, 749-759. Eggers, J. P., Grandgenett, P. M., Collisson, E. C., Lewallen, M. E., Tremayne, J., Singh, P. K., Swanson, B. J., Andersen, J. M., Caffrey, T. C., High, R. R., et al. (2011). Cyclin-dependent kinase 5 is amplified and overexpressed in pancreatic cancer and activated by mutant K-Ras. Clin Cancer Res 17, 6140-6150. Eugene Lin, M.-C. C., Chih-Yang Huang, Shih-Lan Hsu, William J. Huang, Mao-Sheng Lin, Jungle Chi-Hsiang Wu, Ho Lin (2014). All-Trans Retinoic Acid Induces DU145 Cell Cycle Arrest through Cdk5 Activation. Cellular Physiology and Biochemistry 33, 1620-1630. Feldmann, G., Mishra, A., Hong, S. M., Bisht, S., Strock, C. J., Ball, D. W., Goggins, M., Maitra, A., and Nelkin, B. D. (2010). Inhibiting the cyclin-dependent kinase CDK5 blocks pancreatic cancer formation and progression through the suppression of Ras-Ral signaling. Cancer Res 70, 4460-4469. Gartel, A. L., and Radhakrishnan, S. K. (2005). Lost in transcription: p21 repression, mechanisms, and consequences. Cancer Res 65, 3980-3985. Golubovskaya, V. M., Figel, S., Ho, B. T., Johnson, C. P., Yemma, M., Huang, G., Zheng, M., Nyberg, C., Magis, A., Ostrov, D. A., et al. (2012). A small molecule focal adhesion kinase (FAK) inhibitor, targeting Y397 site: 1-(2-hydroxyethyl)-3, 5, 7-triaza-1-azoniatricyclo [,7)]decane; bromide effectively inhibits FAK autophosphorylation activity and decreases cancer cell viability, clonogenicity and tumor growth in vivo. Carcinogenesis 33, 1004-1013. Goodyear, S., and Sharma, M. C. (2007). Roscovitine regulates invasive breast cancer cell (MDA-MB231) proliferation and survival through cell cycle regulatory protein cdk5. Exp Mol Pathol 82, 25-32. Hemelt, M., Yamamoto, H., Cheng, K. K., and Zeegers, M. P. (2009). The effect of smoking on the male excess of bladder cancer: a meta-analysis and geographical analyses. Int J Cancer 124, 412-419. Hsu, F. N., Chen, M. C., Chiang, M. C., Lin, E., Lee, Y. T., Huang, P. H., Lee, G. S., and Lin, H. (2011a). Regulation of androgen receptor and prostate cancer growth by cyclin-dependent kinase 5. J Biol Chem 286, 33141-33149. Hsu, F. N., Chen, M. C., Lin, K. C., Peng, Y. T., Li, P. C., Lin, E., Chiang, M. C., Hsieh, J. T., and Lin, H. (2013). Cyclin-dependent kinase 5 modulates STAT3 and androgen receptor activation through phosphorylation of Ser727 on STAT3 in prostate cancer cells. Am J Physiol Endocrinol Metab 305, E975-986. Hsu, F. N., Yang, M. S., Lin, E., Tseng, C. F., and Lin, H. (2011b). The significance of Her2 on androgen receptor protein stability in the transition of androgen requirement in prostate cancer cells. Am J Physiol Endocrinol Metab 300, E902-908. Kim, E., Chen, F., Wang, C. C., and Harrison, L. E. (2006). CDK5 is a novel regulatory protein in PPARgamma ligand-induced antiproliferation. Int J Oncol 28, 191-194. Kuo, H. S., Hsu, F. N., Chiang, M. C., You, S. C., Chen, M. C., Lo, M. J., and Lin, H. (2009). The role of Cdk5 in retinoic acid-induced apoptosis of cervical cancer cell line. Chin J Physiol 52, 23-30. Levine, A. J. (1997). p53, the cellular gatekeeper for growth and division. Cell 88, 323-331. Lin, H. (2009). The versatile roles of cyclin-dependent kinase 5 in human diseases. Adaptive Medicine 1, 22-25. Lin, H., Chen, M. C., Chiu, C. Y., Song, Y. M., and Lin, S. Y. (2007). Cdk5 regulates STAT3 activation and cell proliferation in medullary thyroid carcinoma cells. J Biol Chem 282, 2776-2784. Lin, H., Chen, M. C., and Ku, C. T. (2009). Cyclin-dependent kinase 5 regulates steroidogenic acute regulatory protein and androgen production in mouse Leydig cells. Endocrinology 150, 396-403. Lin, H., Juang, J. L., and Wang, P. S. (2004). Involvement of Cdk5/p25 in digoxin-triggered prostate cancer cell apoptosis. J Biol Chem 279, 29302-29307. Liu, J. L., Wang, X. Y., Huang, B. X., Zhu, F., Zhang, R. G., and Wu, G. (2011). Expression of CDK5/p35 in resected patients with non-small cell lung cancer: relation to prognosis. Med Oncol 28, 673-678. Musa, F. R., Takenaka, I., Konishi, R., and Tokuda, M. (2000). Effects of luteinizing hormone, follicle-stimulating hormone, and epidermal growth factor on expression and kinase activity of cyclin-dependent kinase 5 in Leydig TM3 and Sertoli TM4 cell lines. J Androl 21, 392-402. Musa, F. R., Tokuda, M., Kuwata, Y., Ogawa, T., Tomizawa, K., Konishi, R., Takenaka, I., and Hatase, O. (1998). Expression of cyclin-dependent kinase 5 and associated cyclins in Leydig and Sertoli cells of the testis. J Androl 19, 657-666. Oyama, T., Kanai, Y., Ochiai, A., Akimoto, S., Oda, T., Yanagihara, K., Nagafuchi, A., Tsukita, S., Shibamoto, S., Ito, F., and et al. (1994). A truncated beta-catenin disrupts the interaction between E-cadherin and alpha-catenin: a cause of loss of intercellular adhesiveness in human cancer cell lines. Cancer Res 54, 6282-6287. Ozawa, M., Baribault, H., and Kemler, R. (1989). The cytoplasmic domain of the cell adhesion molecule uvomorulin associates with three independent proteins structurally related in different species. The EMBO journal 8, 1711-1717. Pagano, M., Pepperkok, R., Verde, F., Ansorge, W., and Draetta, G. (1992). Cyclin A is required at two points in the human cell cycle. The EMBO journal 11, 961-971. Pan, M. H., and Ho, C. T. (2008). Chemopreventive effects of natural dietary compounds on cancer development. Chemical Society reviews 37, 2558-2574. Patrick, G. N., Zukerberg, L., Nikolic, M., de la Monte, S., Dikkes, P., and Tsai, L. H. (1999). Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature 402, 615-622. Polyak, K., Lee, M. H., Erdjument-Bromage, H., Koff, A., Roberts, J. M., Tempst, P., and Massague, J. (1994). Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell 78, 59-66. Ridley, A. J. (2001). Rho GTPases and cell migration. Journal of cell science 114, 2713-2722. Rodriguez, R., and Meuth, M. (2006). Chk1 and p21 cooperate to prevent apoptosis during DNA replication fork stress. Molecular biology of the cell 17, 402-412. Schuman, E. M., and Murase, S. (2003). Cadherins and synaptic plasticity: activity-dependent cyclin-dependent kinase 5 regulation of synaptic beta-catenin-cadherin interactions. Philosophical transactions of the Royal Society of London Series B, Biological sciences 358, 749-756. Selvendiran, K., Koga, H., Ueno, T., Yoshida, T., Maeyama, M., Torimura, T., Yano, H., Kojiro, M., and Sata, M. (2006). Luteolin promotes degradation in signal transducer and activator of transcription 3 in human hepatoma cells: an implication for the antitumor potential of flavonoids. Cancer Res 66, 4826-4834. Shahin, O., Thalmann, G. N., Rentsch, C., Mazzucchelli, L., and Studer, U. E. (2003). A retrospective analysis of 153 patients treated with or without intravesical bacillus Calmette-Guerin for primary stage T1 grade 3 bladder cancer: recurrence, progression and survival. J Urol 169, 96-100; discussion 100. Sherr, C. J. (2000). The Pezcoller lecture: cancer cell cycles revisited. Cancer Res 60, 3689-3695. Smith, M. A., Parkinson, D. R., Cheson, B. D., and Friedman, M. A. (1992). Retinoids in cancer therapy. J Clin Oncol 10, 839-864. Strock, C. J., Park, J. I., Nakakura, E. K., Bova, G. S., Isaacs, J. T., Ball, D. W., and Nelkin, B. D. (2006). Cyclin-dependent kinase 5 activity controls cell motility and metastatic potential of prostate cancer cells. Cancer Res 66, 7509-7515. Tripathi, B. K., and Zelenka, P. S. (2009). Cdk5-dependent regulation of Rho activity, cytoskeletal contraction, and epithelial cell migration via suppression of Src and p190RhoGAP. Mol Cell Biol 29, 6488-6499. Tripathi, B. K., and Zelenka, P. S. (2010). Cdk5: A regulator of epithelial cell adhesion and migration. Cell adhesion & migration 4, 333-336. Tsai, L. H., Delalle, I., Caviness, V. S., Jr., Chae, T., and Harlow, E. (1994). p35 is a neural-specific regulatory subunit of cyclin-dependent kinase 5. Nature 371, 419-423. Ueda, T., Bruchovsky, N., and Sadar, M. D. (2002a). Activation of the androgen receptor N-terminal domain by interleukin-6 via MAPK and STAT3 signal transduction pathways. J Biol Chem 277, 7076-7085. Ueda, T., Mawji, N. R., Bruchovsky, N., and Sadar, M. D. (2002b). Ligand-independent activation of the androgen receptor by interleukin-6 and the role of steroid receptor coactivator-1 in prostate cancer cells. J Biol Chem 277, 38087-38094. Upadhyay, A. K., Ajay, A. K., Singh, S., and Bhat, M. K. (2008). Cell cycle regulatory protein 5 (Cdk5) is a novel downstream target of ERK in carboplatin induced death of breast cancer cells. Curr Cancer Drug Targets 8, 741-752. Weishaupt, J. H., Neusch, C., and Bahr, M. (2003). Cyclin-dependent kinase 5 (CDK5) and neuronal cell death. Cell and tissue research 312, 1-8. Wu, J. T., Han, B. M., Yu, S. Q., Wang, H. P., and Xia, S. J. (2010). Androgen receptor is a potential therapeutic target for bladder cancer. Urology 75, 820-827. Xie, Z., and Tsai, L. H. (2004). Cdk5 phosphorylation of FAK regulates centrosome-associated miocrotubules and neuronal migration. Cell cycle 3, 108-110. Yeh, J. Y., Huang, W. J., Kan, S. F., and Wang, P. S. (2001). Inhibitory effects of digitalis on the proliferation of androgen dependent and independent prostate cancer cells. J Urol 166, 1937-1942.
Prostate cancer is the most common malignancy among men and bladder cancer is the fourth most common malignancy among men in the United States. In Taiwan, prostate cancer and bladder cancer also play an important role in male urinary tract malignancies. Recent studies have explored the roles of cyclin-dependent kinase 5 (Cdk5) and its activator p35 in cancer research. We previously suggested that Cdk5 regulates the proliferation of prostate and thyroid cancer cells; thus, the aim of this thesis is to investigate the relation between Cdk5/p35 protein expression and the biophysical function in prostate and bladder cancer cells.

Part I: The overexpression of cyclin-dependent kinase 5 and p35 in urinary bladder urothelial carcinoma and associated with bladder cancer cells migration activity

We collected bladder cancer specimens from 27 patients (admitted by Institutional Review Board of Chang Bing Show Chwen Memorial Hospital). The levels of Cdk5 and p35 protein were analyzed using immunohistochemical staining or western blotting and compared between tumors and adjacent non-cancerous bladder tissues from individual patient. Migration array was conducted using bladder cancer cell line T24 in while Cdk5 was overexpressed or inhibited by inhibitor. The data indicated that the levels of Cdk5 and p35 protein expression were higher in tumors compared with the adjacent normal bladder tissues in 18 out of 27 patients. In addition, Cdk5 overexpression increased the migration activity of bladder cancer cell line T24 and the migration can be inhibited by treating with the Cdk5 inhibitor, roscovitine (p < 0.05). We first report the overexpression of Cdk5 and p35 proteins in bladder cancer specimens. These findings suggest that Cdk5 might be a tumor marker of bladder cancer and respond to regulate cell migration. Thus, these findings should help future bladder cancer diagnosis and treatment.

Part II: Cyclin-dependent kinase 5 and p35 protein expressions were associated with prostate cancer grade and stage

Prostate cancer is the most frequently diagnosed cancer and second leading cause of cancer-related deaths in men. The roles of cyclin-dependent kinase 5 (Cdk5) and its activator p35 in cancer biology have been extensively studied. We previously demonstrated that Cdk5 may regulate proliferation of prostate and thyroid cancer cells. The aim of this study was to investigate the relationship between Cdk5 and p35 protein expressions and prostate cancer cell grade and stage. We collected 212 patient specimens of prostate cancer from commercial tissue array. Cdk5 and p35 protein levels were evaluated by immunohistochemical staining. The images were double-blind evaluated by two experts in accordance with a scoring system based on the intensity and distribution of staining signals. The correlations between Cdk5 and p35 protein levels and tumor grade or stages were analyzed using Fisher's exact test. The overexpression of Cdk5/p35 was significantly correlated with prostate cancer grade (p = 0.0277) as well as stage (p = 0.0150). A higher grade and stage of prostate cancer was associated with higher expressions of Cdk5 and p35 proteins. This study first identified overexpression of Cdk5 and p35 in prostate cancer using tissue array specimens, which implies that Cdk5 is a potential tumor marker of prostate cancer. These findings may help making early diagnosis of prostate cancer and in the development of new treatments in the future.

To sum up the conclusions of part I and part II, we indicate the role of Cdk5 and p35 in bladder cancer and prostate cancer. By investigating on the expression of Cdk5 and p35 proteins, we explored the potential roles of Cdk5 and p35 proteins in prostate cancer and bladder cancer. We look forward to the further cell biology evidence to demonstrate the mechanism of Cdk5 and p35 proteins in tumors of prostate and bladder.


第一部份: Cdk5蛋白質在膀胱癌之表現及與膀胱癌細胞遷移活性之關係


第二部份: Cdk5及p35蛋白之過度表現與前列腺癌細胞惡性度及期別相關

前列腺癌是美國男性最常見的癌症和第二大癌症相關死亡的原因。Cdk5蛋白及活化子p35的作用於癌症生物學已被廣泛研究;根據我們之前發表之文獻指出,Cdk5基因可調節前列腺癌和甲狀腺癌細胞的增生。本研究的目的是觀察Cdk5和p35蛋白表現與前列腺癌的細胞惡性度和分期之間的關係。我們利用市售的組織微陣列切片觀察了212個前列腺癌組織標本。Cdk5和p35蛋白表現以組織免疫染色評估。這些影像由兩位專家以雙盲之模式,依據染色信號強度和分佈的評分系統加以評估。Cdk5和p35蛋白表現與腫瘤的細胞惡性度和分期之間的相關性採用Fisher精確檢驗統計。結果顯示,Cdk5和P35蛋白的表現與前列腺癌細胞惡性度(p = 0.0277)或分期(p = 0.0150)呈現顯著地相關性,亦即較高細胞惡性度和分期的前列腺癌有較高的Cdk5和P35蛋白之表現。由此推論, Cdk5可能是前列腺癌的一個潛在腫瘤標記物,配合本團隊已發表的文獻可知,抑制Cdk5蛋白表現或活性可抑制前列腺癌的生長。希望這些發現未來有助於使前列腺癌的早期診斷和發展新的治療方法。
Rights: 同意授權瀏覽/列印電子全文服務,2017-06-30起公開。
Appears in Collections:生命科學系所

Files in This Item:
File SizeFormat Existing users please Login
nchu-103-8097052202-1.pdf1.91 MBAdobe PDFThis file is only available in the university internal network    Request a copy
Show full item record

Google ScholarTM


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