Glucocorticoid induced leucine zipper inhibits apoptosis of cardiomyocytes by doxorubicin.
Doxorubicin (Dox) is an indispensable chemotherapeutic agent for the treatment of various forms of neoplasia such as lung, breast, ovarian, and bladder cancers. Cardiotoxicity is a major concern for patients receiving Dox therapy. Previous work from our laboratory indicated that glucocorticoids (GCs) alleviate Dox-induced apoptosis in cardiomyocytes. Here we have found glucocorticoid-induced leucine zipper (GILZ) to be a mediator of GC-induced cytoprotection. GILZ was found to be induced in cardiomyocytes by GC treatment. Knocking down of GILZ using siRNA resulted in cancelation of GC-induced cytoprotection against apoptosis by Dox treatment. Overexpressing GILZ by transfection was able to protect cells from apoptosis induced by Dox as measured by caspase activation, Annexin V binding and morphologic changes. Western blot analyses indicate that GILZ overexpression prevented cytochrome c release from mitochondria and cleavage of caspase-3. When bcl-2 family proteins were examined, we found that GILZ overexpression causes induction of the pro-survival protein Bcl-xL. Since siRNA against Bcl-xL reverses GC induced cytoprotection, Bcl-xL induction represents an important event in GILZ-induced cytoprotection. Our data suggest that GILZ functions as a cytoprotective gene in cardiomyocytes.
The University of Arizona, Department of Pharmacology, 1501 N Campbell Ave., Tucson, AZ 85724, USA.
David
D
Aguilar
The University of Arizona, Department of Pharmacology, 1501 N Campbell Ave., Tucson, AZ 85724, USA.
Joshua
J
Strom
The University of Arizona, Department of Pharmacology, 1501 N Campbell Ave., Tucson, AZ 85724, USA. Electronic address: qchen@email.arizona.edu.
Qin M
QM
Chen
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects; D017209:Apoptosis / Q000187:drug effects*; D002316:Cardiotonic Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D054715:Cardiotoxins / Q000009:adverse effects / Q000037:antagonists & inhibitors*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003345:Corticosterone / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004317:Doxorubicin / Q000009:adverse effects / Q000037:antagonists & inhibitors*; D005938:Glucocorticoids / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D014157:Transcription Factors / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D051020:bcl-X Protein / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; C494813:Bcl2l1 protein, rat; D002316:Cardiotonic Agents; D054715:Cardiotoxins; C498608:Dsip1 protein, mouse; D005938:Glucocorticoids; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D014157:Transcription Factors; C498609:Tsc22d3 protein, rat; D051020:bcl-X Protein; D004317:Doxorubicin; D003345:Corticosterone
Bcl-xL; Caspase-3; Cell death; Chemotherapy; Nuclear receptor; Steroids