This renewal application requests support to extend studies of the regulation of drug resistance and tumor progression by redox conditions. The long-term objectives of this application are to develop effective use of chemotherapeutic agents for the treatment of human malignancies, thereby improving the cure rates of human cancers. This is consistent with the mission of National Cancer Institute. Studies from the previous funding years have established that gamma-glutamylcysteine synthesis (gamma-GCS), which is the rate-limiting enzyme for the biosynthesis of glutathione (GSH), is an important regulator of intracellular redox conditions. Overexpression of a heavy subunit of gamma-GCS (gamma-GCSh) reduces intracellular redox conditions, as a consequence, changes the expression profile of a whole host of genes involved in drug resistance (MDR1, MRP1, MRP3, and HCtr1) and tumor progression (MMP1, MMP3, and MMP10). Thus, understanding mechanisms that regulate gamma-GCS expression is important in cancer pharmacology and tumor biology. Whereas transcriptional regulation of gamma-GCSh by cytotoxic agents has been studied quite extensively, posttranscriptional regulation has not been investigated in detail. We recently observed that a novel posttranscriptional regulation mechanism of enhancement of mRNA stability is important for the upregulation of gamma-GCSh under various oxidative stress conditions. This renewal application proposes in Specific Aim 1 to elucidate the hypothesis that redox-regulated gamma-GCSh mRNA stability is mediated by the MAPK pathway. Approaches to testing the hypothesis that the MAPK pathway is also involved in the down regulation of MMP expression by overexpression of gamma-GCSh are proposed in Specific Aim 2. Strikingly, elevated expression of gamma-GCSh is associated with upregulation of the copper transporter hCtr1, which transport cisplatin into cultured cells. We therefore propose in Specific Aim 3 to investigate the regulation mechanism of hCtr1 under various redox conditions. We hope from these studies to learn the molecular bases of redox conditions that affect drug sensitivity through the regulation of their respective drug resistance gene expression. ? ?

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Special Emphasis Panel (ZRG1-ONC-F (03))
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Forry, Suzanne L
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University of Texas MD Anderson Cancer Center
Other Domestic Higher Education
United States
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Kuo, Macus Tien; Savaraj, Niramol; Feun, Lynn G (2010) Targeted cellular metabolism for cancer chemotherapy with recombinant arginine-degrading enzymes. Oncotarget 1:246-51
Tsai, Wen-Bin; Aiba, Isamu; Lee, Soo-yong et al. (2009) Resistance to arginine deiminase treatment in melanoma cells is associated with induced argininosuccinate synthetase expression involving c-Myc/HIF-1alpha/Sp4. Mol Cancer Ther 8:3223-33
Kuo, Macus Tien (2009) Redox regulation of multidrug resistance in cancer chemotherapy: molecular mechanisms and therapeutic opportunities. Antioxid Redox Signal 11:99-133
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Wangpaichitr, Medhi; Wu, Chunjing; You, Min et al. (2008) Inhibition of mTOR restores cisplatin sensitivity through down-regulation of growth and anti-apoptotic proteins. Eur J Pharmacol 591:124-7
Song, Im-Sook; Chen, Helen H W; Aiba, Isamu et al. (2008) Transcription factor Sp1 plays an important role in the regulation of copper homeostasis in mammalian cells. Mol Pharmacol 74:705-13
Aiba, Isamu; Hossain, Anwar; Kuo, Macus Tien (2008) Elevated GSH level increases cadmium resistance through down-regulation of Sp1-dependent expression of the cadmium transporter ZIP8. Mol Pharmacol 74:823-33
Chen, Helen H W; Song, Im-Sook; Hossain, Anwar et al. (2008) Elevated glutathione levels confer cellular sensitization to cisplatin toxicity by up-regulation of copper transporter hCtr1. Mol Pharmacol 74:697-704
Kuo, Macus Tien; Chen, Helen H W; Song, Im-Sook et al. (2007) The roles of copper transporters in cisplatin resistance. Cancer Metastasis Rev 26:71-83
Kuo, M Tien (2007) Roles of multidrug resistance genes in breast cancer chemoresistance. Adv Exp Med Biol 608:23-30

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