Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.5.1.18 (glutathione S-transferase)
 22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Medullary thyroid carcinoma (MTC) is a cancer that is relatively insensitive to clinical chemotherapy. Our previous studies have demonstrated that an established human MTC cell line, TT, seems to possess an intrinsic resistance phenotype when tested for its chemosensitivity to multiple antineoplastic agents. We now report our investigation on the potential mechanisms responsible for the chemoresistance of TT cells. Northern analysis showed an increased level of multidrug resistance gene (mdrl) mRNA in TT and in an inherently drug-resistant colon carcinoma cell line, LoVo, when compared with CEM, a drug-sensitive leukemic lymphoblastic cell line; the latter two cell lines were included here as a control. Verapamil (10 microM) partially reversed resistance to doxorubicin in TT and LoVo cells, but had no effect on doxorubicin cytotoxicity to CEM cells. Expression of glutathione-S-transferase-pi (GST pi) gene was undetectable in TT, whereas, under similar conditions, GST pi mRNA was detectable in LoVo. Growth kinetics studies revealed that doubling times of the 3 cell lines in exponential growth were 95, 37, and 24 h for TT, LoVo and CEM, respectively. Flow-cytometric analysis showed that the percentage of TT population is S phase was 49% and 33% of the LoVo and CEM cell populations, respectively, while the G1/G0 fraction of TT was about 63% and 61% higher than that of LoVo and CEM, respectively. Our data suggest that the intrinsic chemoresistance in TT cells may be attributed to the combined factors of overexpression of the mdrl gene, a slower growth rate and a smaller proliferation fraction, although other factors or mechanisms that are yet to be investigated may also act in concert to contribute to the resistance phenotype of TT.
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PMID:Intrinsic drug resistance in a human medullary thyroid carcinoma cell line: association with overexpression of mdrl gene and low proliferation fraction. 188 39

Medullary thyroid carcinoma (MTC) is frequently resistant to chemotherapy. In this work, we have studied the effect of cisdiamminedichloroplatinum (II) (CDDP) in six MTC human cell lines and we have tried to reverse the resistance to CDDP with amphotericin B (AmB). We also studied the metabolism of glutathione (GSH) and the presence of the glutathione-sulfotransferase pi (GST pi) mRNA in the MTC cell lines. The cisplatin-induced cytotoxicity was evaluated with the 3-4,5 dimethylthiazol-2,5 diphenyl tetrazolium bromide (MTT) test, the neutral red (NR) uptake and with total GSH measurement in six cell lines, TT cell line and five cell lines that we isolated. The cultures were performed with or without AmB (5 micrograms/mL). Intracellular GSH was measured in TMC cells and compared to the levels obtained in six normal thyroid tissues. The expression of GST pi mRNA was evaluated by Northern blotting in the different cell lines. A CDDP-induced cytotoxicity was obtained in the six cell lines at doses inhibiting 50% of the cellular proliferation (IC50) varying from 6 to 40 micrograms according to the tests and the cells tested. A low concentration of AmB (5 micrograms/mL) potentiated the cisplatin toxicity after a 48-h coincubation of TMC in all cases. GSH levels in TMC cell lines were identical to those found in normal cells. GST pi mRNA was detected in all the TMC lines, except in TT cell line. In conclusion, CDDP was toxic for all the TMC cell lines and AmB potentiated this antitumoral effect. On the contrary, GSH and GST pi do not seem to be involved in the mechanisms of the resistance in these cell lines.
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PMID:[Modulation of cisplatin cytotoxicity by amphotericin B in six human cell lines of medullary thyroid cancer]. 886 41

VHL is part of an SCF related E3-ubiquitin ligase complex with 'gatekeeper' function in renal carcinoma. However, no mutations have been identified in VHL interacting proteins in wild type VHL tumors. We previously reported that the TRC8 gene was interrupted by a t(3;8) translocation in a family with hereditary renal and non-medullary thyroid cancer. TRC8 encodes a multi-membrane spanning protein containing a RING-H2 finger with in vitro ubiquitin ligase activity. We isolated the Drosophila homologue, DTrc8, and studied its function by genetic manipulations and a yeast 2-hybrid screen. Human and Drosophila TRC8 proteins localize to the endoplasmic reticulum. Loss of either DTrc8 or DVhl resulted in an identical ventral midline defect. Direct interaction between DTrc8 and DVhl was confirmed by GST-pulldown and co-immunoprecipitation experiments. CSN-5/JAB1 is a component of the COP9 signalosome, recently shown to regulate SCF function. We found that DTrc8 physically interacts with CSN-5 and that human JAB1 localization is dependent on VHL mutant status. Lastly, overexpression of DTrc8 inhibited growth consistent with its presumed role as a tumor suppressor gene. Thus, VHL, TRC8, and JAB1 appear to be linked both physically and functionally and all three may participate in the development of kidney cancer.
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PMID:The TRC8 hereditary kidney cancer gene suppresses growth and functions with VHL in a common pathway. 1203 52