Linked Life Data

17628013

Source:http://linkedlifedata.com/resource/pubmed/id/17628013

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
2007-9-19
pubmed:abstractText
This study aims to investigate the role of gamma-glutamylcysteine synthetase (gamma-GCS), the rate-limiting enzyme for glutathione (GSH) synthesis, in the c-Myc-dependent response to antineoplastic agents. We found that specific c-Myc inhibition depleted cells of GSH by directly reducing the gene expression of both heavy and light subunits of the gamma-GCS enzyme and increased their susceptibility to antineoplastic drugs with different mechanisms of action, such as cisplatin (CDDP), staurosporine (STR), and 5-fluorouracil (5-FU). The effect caused by c-Myc inhibition on CDDP and STR response, but not to 5-FU treatment, is directly linked to the impairment of the gamma-GCS expression, because up-regulation of gamma-GCS reverted drug sensitivity, whereas the interference of GSH synthesis increased drug susceptibility as much as after c-Myc down-regulation. The role of gamma-GCS in the c-Myc-directed drug response depends on the capacity of drugs to trigger reactive oxygen species (ROS) production. Indeed, although 5-FU exposure did not induce any ROS, CDDP- and STR-induced oxidative stress enhanced the recruitment of c-Myc on both gamma-GCS promoters, thus stimulating GSH neosynthesis and allowing cells to recover from ROS-induced drug damage. In conclusion, our data demonstrate that the gamma-GCS gene is the downstream target of c-Myc oncoprotein, driving the response to ROS-inducing drugs. Thus, gamma-GCS impairment might specifically sensitize high c-Myc tumor cells to chemotherapy.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Oct
pubmed:issn
0026-895X
pubmed:author
pubmed:issnType
Print
pubmed:volume
72
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1015-23
pubmed:meshHeading
pubmed:year
2007
pubmed:articleTitle
Gamma-glutamylcysteine synthetase mediates the c-Myc-dependent response to antineoplastic agents in melanoma cells.
pubmed:affiliation
Experimental Chemotherapy Laboratory, Experimental Research Center, Regina Elena Cancer Institute, Via delle Messi d'Oro 156, 00158 Rome, Italy.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't