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Macus T. Kuo, Ph.D.

Present Title & Affiliation

Primary Appointment

Felix L. Hass Professor in Basic Science, Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX

Research Interests

Research Interests

 

We currently have two major research programs in our laboratory:

 

(A)  Improving the Therapeutic Efficacy of Platinum-Based Antitumor Agents

 

Platinum (Pt)-based antitumor agents have significant antitumor activity in the treatments of many human malignancies.  Especially in ovarian cancers and in testicular germ cell tumors, cisplatin (Cp)-based combination chemotherapy has been a pillar of drug therapy of these diseases.  However, resistance to these agents is the major cause of treatment failure. While it has been recognized that multiple mechanisms are involved in Cp resistance, one important mechanism of resistance is defective in drug transport.  Recent studies have indicated that the human high-affinity copper (Cu) transporter 1 (hCtr1) is a functional transporter of cisplatin and its analogues, carboplatin, and oxaliplatin.  Results from our laboratory have demonstrated that many established cisplatin (Cp)-resistant (CpR) cell lines exhibit reduced expression levels of hCtr1 compared with their matched parental cell lines.  These CpR cell lines can be re-sensitized to Cp treatment by overexpressing hCtr1 in these cells.  Our research interest has been the molecular mechanisms of hCtr1 regulation in mammalian system.  Copper is an essential micronutrient that is required for cell survival; yet Cu overload is toxic.  To meet their need for copper while avoiding copper toxicity, all living organisms from yeast to humans have developed an evolutionarily conserved system to regulate copper homeostasis.  We have been investigating mechanisms of hCtr1 regulation by copper homeostasis and how copper homeostatic regulation affects cancer cells to response to platinum-based antitumor drugs.

 

(B)       Improving the Chemotherapeutic Efficacy of Melanoma by Antitumor Agent Arginine Deiminase

Malignant melanoma of the skin can be highly lethal when the disease is detected in the advanced stages. Currently, overall cure rate for advanced melanoma is <10%.   It has been demonstrated that a great majority of malignant melanoma is autotrophic for arginine, due to the fact that these melanoma cells do not express argininosuccinate synthetase (AS), the rate-limiting enzyme for the biosynthesis of arginine from citrulline.  These AS-negative melanoma cells require arginine from extracellular sources for survival.  When these melanoma cells are exposed to arginine deiminase (ADI) which degrades arginine to citrulline and ammonia, they become arginine starvation, leading to cell death; while normal cells which express AS are able to survive.   ADI is a bacterial enzyme and a pegylated enzyme (ADI-PEG20) has been developed.  Favorable results from Phase I and Phase II clinical trials using ADI-PEG20 for advanced melanoma have been obtained.  It has been learned from clinical studies that not all the patients who are negative for AS expression responded to the ADI-PEG20 treatment.  Re-expressed AS has been observed in the ADI-insensitive patients.   Our research interest is the molecular mechanisms involved in the induced AS expression in melanoma cells exposed to ADI-PEG20 and to develop strategies to overcome drug resistance associated with AS induction thereby improving the efficacy of in melanoma cancer chemotherapy using ADI-PEG20.

 

Office Address

The University of Texas MD Anderson Cancer Center
7435 Fannin Street
Unit Number: Unit 951
Houston, TX 77054
Room Number: 2SCR4.3025
Phone: (713) 834-6038
Fax: (713) 834-6084
Email: tkuo@mdanderson.org

Education & Training

Degree-Granting Education

1973 The University of Texas, Graduate School of Biomedical Sciences at Houston, Houston, TX, PHD, Molecular Biology
1971 National Taiwan University, Taipei, Taiwan, MS, Plant Pathology
1968 National Taiwan University, Taipei, Taiwan, BS, Plant Pathology

Postgraduate Training

1/1973-1/1976 Project Investigator, Department of Developmental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX

Experience/Service

Academic Appointments

Professor, Department of Molecular Pathology, Division of Pathology/Lab Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 9/1993-present
Associate Professor of Pathology (Biology) and Associate Biologist (Pathology), Division of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, 9/1983-8/1993
Member, The University of Texas Health Science Center, Graduate School of Biomedical Sciences, Houston, TX, 9/1980-present
Assistant Biologist and Assistant Professor of Biology, Department of Cell Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, 9/1979-9/1983
Research Associate, Department of Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, 9/1976-8/1979

Selected Publications

Peer-Reviewed Original Research Articles

1. Chen HH, Yan JJ, Chen WC, Kuo MT, Lai YH, Lai WW, Liu HS, Su WC. Predictive and prognostic value of human copper transporter 1 (hCtr1) in patients with stage III non-small-cell lung cancer receiving first-line platinum-based doublet chemotherapy. Lung Cancer 75(2):228-34, 2/2012. e-Pub 7/23/2011. PMID: 21788094.
2. Guan X, Wang Y, Xie R, Chen L, Bai J, Lu J, Kuo MT. p27Kip1 as a prognostic factor in breast cancer: a systematic review and meta-analysis. J Cell Mol Med 14(4):944-953, 4/2010. e-Pub 2/27/2010. PMID: 19298520.
3. You M, Savaraj M, Wangpaichir M, Wu C, Kuo MT, Varona-Santos J, Nguyen DM, Feun L. The combination of ADI-PEG20 and TRAIL effectively increases cell death in melanoma cell lines. Biochem Biophys Res Commun 394:760-766, 2010.
4. Liang ZD, Stockton D, Savaraj N, Tien Kuo M. Mechanistic comparison of human cooper transporter hCtr1-mediated transports between copper ion and cisplatin. Mol Pharmacol 76(4):843-853, 10/2009. e-Pub 7/2009. PMCID: PMC2769054.
5. Tsai WB, Aiba I, Lee SY, Feun L, Savaraj N, Kuo MT. Resistance to arginine deiminase treatment in melanoma cells is associated with induced argininosuccinate synthetase expression involving c-Myc/HIF{alpha}/Sp4. Mol Cancer Ther 8(12):3223-3233, 2009. PMCID: PMC2795119.
6. Chen HH, Song IS, Hossain A, Choi MK, Yamane Y, Liang ZD, Lu J, Wu LY, Siddik ZH, Klomp LW, Savaraj N, Kuo MT. Elevated glutathione levels confer cellular sensitization to cisplatin toxicity by upregulation of copper transporter hCtr1. Mol Pharmacol 74(3):697-704, 9/2008. e-Pub 6/2008. PMCID: PMC2583459.
7. Song IS, Chen HH, Aiba I, Hossain A, Liang ZD, Klomp LW, Kuo MT. Transcription factor Sp1 plays an important role in the regulation of copper homeostasis in mammalian cells. Mol Pharmacol 74(3):705-713, 9/2008. e-Pub 5/2008. PMCID: PMC2574735.
8. Wangpaichitr M, Wu C., You M, Kuo MT, Feun L, Lampidis T, Savaraj N. Inhibition of mTOR restores cisplatin sensitivity through downregulation of growth and anti-apoptotic proteins. Euro J Pharmacol 591:124-127, 2008.
9. Adachi T, Nakagawa H, Chung I, Hagiya Y, Hoshijima K, Noguchi N, Kuo MT, Ishikawa T. Nrf2-dependent and -independent induction of ABC transporters ABCC1, ABCC2, and ABCG2 in HepG2 cells under oxidative stress. Journal of Experimental Therapeutics and Oncology 6:335-348, 2007.
10. Savaraj N, Wu C, Kuo MT, You M, Wangpaichitr M, Robles C, Spector S, and Feun L. The relationship of arginine deprivation, argininosuccinate synthetase and cell death in melanoma. Drug Target Insights 2:119-128, 2007.
11. Hossain A, Kuo MT, Saunders GF. Mir-17-5p regulates breast cancer cell proliferation by inhibiting translation of AIB1 mRNA. Mol Cell Biol 26:8191-8201, 11/2006. PMID: 16940181.
12. Hossain A, Nixon M, Kuo MT, Saunders GF. N-terminally truncated WT1 protein with oncogenic properties overexpressed in leukemia. J Biol Chem 281:28122-28130, 9/2006. PMID: 16698800.
13. Kuo MT, Wei Y, Yang X, Tatebe S, Liu J, Troncoso P, Sahin A, Ro JY, Hamilton SR, and Savaraj N. Association of fragile site-associated (FSA) gene expression with epithelial differentiation and tumor development. Biochem Biophy Res Commu 340:887-893, 2006.
14. Wei Y, Lin-Lee YC, Yang X, Dai W, Zhao S, Rassool FV, Elgart GW, Feun L, Savaraj N, and Kuo MT. Molecular cloning of Chinese hamster 1q31 chromosomal fragile site DNA that is important to mdr1 gene amplification reveals a novel gene whose expression is associated with spermatocyte and adipocyte differentiation. Gene 372:44-52, 2006.
15. Kuo MT, and Savaraj N. Roles of reactive oxygen species in hepatocarcinogenesis and drug resistance gene expression in liver cancers. Mol Carcinog 45:701-709, 2006.
16. Song IS, Tatebe S, Dai W, Kuo MT. Delayed mechanism for induction of gamma-glutamylcysteine synthetase heavy subunit mRNA stability by oxidative stress involving p38 mitogen-activated protein kinase signaling. J Biol Chem 280(31):28230-40, 8/2005. PMID: 15946948.
17. Wu C, Wangpaichitr M, Feun LG, Kuo MT, Robles C, Lampidis T, and Savaraj N. Overcoming cisplatin resistance by mTOR inhibitor in Lung Cancer. Mol Cancer 4:25, 2005.
18. Savaraj N, Wu C, Landy H, Wangpaijit M, Wei Y, Kuo MT, Robles C, Fust AJ, Lampidis T, and Feun L. Procollagen alpha 1 type I: potential aide in hispathological grading of glioma. Cancer Invest 23:577-581, 2005.
19. Savaraj N, Wei Y, Unate U, Liu P-M, Wu CJ, Wangpaichitr M, Xia D, Xu H-J, Hu S-X, Kuo MT. Redox regulation of matrix metalloproteinase gene family in small cell lung cancer cells. Free Radicals Res 39:373-381, 2005.
20. Song IS, Savaraj N, Siddik ZH, Liu P, Wei Y, Wu CJ, Kuo MT. Role of human copper transporter Ctr1 in the transport of platinum-based antitumor agents in cisplatin-sensitive and cisplatin-resistant cells. Mol Cancer Ther 3(12):1543-9, 12/2004. PMID: 15634647.
21. Takayanagi S, Kataoka T, Ohara O, Oishi M, Kuo MT, Ishikawa T. Human ATP-binding cassette transporter ABCC10: expression profile and p53-dependent upregulation. J Exp Ther Oncol 4(3):239-46, 10/2004. PMID: 15724843.
22. Lin-Lee YC, Tatebe S, Savaraj N, Ishikawa T, Tien Kuo M. Differential sensitivities of the MRP gene family and gamma-glutamylcysteine synthetase to prooxidants in human colorectal carcinoma cell lines with different p53 status. Biochem Pharmacol 61(5):555-63, 3/2001. PMID: 11239498.

Invited Articles

1. Kuo MT, Savaraj N, Feun LG. Targeted cellular metabolism for cancer chemotherapy with recombinant arginine-degrading enzymes. Oncotarget 1(4):246-251, 8/2010. PMCID: PMC2998341.
2. Chen HH, Kuo MT. Role of glutathione in the regulation of cisplatin resistance in cancer chemotherapy. Met Based Drugs 2010:1-7, 2010. e-Pub 9/2010. PMCID: PMC2946579.
3. Kuo MT. Redox regulation of multidrug resistance in cancer chemotherapy: Molecular mechanisms and therapeutic opportunities. Antioxid Redox Signal 11(11):99-134, 1/2009. PMCID: PMC2577715.
4. Feun L, You M, Wu CJ, Kuo MT, Wangpaichitr M, Spector S, Savaraj N. Arginine deprivation as a targeted therapy for cancer. Curr Pharmaceut Design 14:1049-1057, 2008.
5. Toyoda Y, Hagiya Y, Adachi T, Hoshijima K, Kuo MT, Ishikawa T. MRP class of human ATP binding cassette (ABC) transporters: historical background and new research directions. Xenobiotica 37:833-862, 2008.
6. Kuo MT, Chen HHW, Song IS, Savaraj N, Ishikawa T. The roles of copper transporters in cisplatin resistance. Cancer Metastasis Rev 26:71-83, 2/2007. PMID: 17318448.
7. Kuo MT. Roles of multidrug resistance genes in breast cancer chemoresistance. In "Breast Cancer Chemosensitivity", Yu D and Hung MC (ed). Landes/Eurechls, New York, NY:23-30, 2007.
8. Kuo MT. Roles of multidrug resistance genes in breast cancer resistance. Advance Exp Med Biol 608:23-30, 2007.

Book Chapters

1. Savaraj N, You M, Wu C, Kuo MT, Dinh V, Wangpaichitr M, Feun L. Targeting Argininosuccinate Synthetase in Cancer Therapy. In: In Cell Signaling & Molecular Targets in Cancer. Ed(s) Chatterjee M, Kashfi K, 37-49, 2012.

Last updated: 8/1/2013