Document Detail

Nifedipine prevents etoposide-induced caspase-3 activation, prenyl transferase degradation and loss in cell viability in pancreatic β-cells.
MedLine Citation:
PMID:  23054080     Owner:  NLM     Status:  MEDLINE    
Emerging evidence implicates novel roles for post-translational prenylation (i.e., farnesylation and geranylgeranylation) of various signaling proteins in a variety of cellular functions including hormone secretion, survival and apoptosis. In the context of cellular apoptosis, it has been shown previously that caspase-3 activation, a hallmark of mitochondrial dysregulation, promotes hydrolysis of several key cellular proteins. We report herein that exposure of insulin-secreting INS 832/13 cells or normal rat islets to etoposide leads to significant activation of caspase-3 and subsequent degradation of the common α-subunit of farnesyl/geranylgeranyl transferases (FTase/GGTase). Furthermore, the above stated signaling steps were prevented by Z-DEVD-FMK, a known inhibitor of caspase-3. In addition, treatment of cell lysates with recombinant caspase-3 also caused FTase/GGTase α-subunit degradation. Moreover, nifedipine, a calcium channel blocker, markedly attenuated etoposide-induced caspase-3 activation, FTase/GGTase α-subunit degradation in INS 832/13 cells and normal rat islets. Further, nifedipine significantly restored etoposide-induced loss in metabolic cell viability in INS 832/13 cells. Based on these findings, we conclude that etoposide induces loss in cell viability by inducing mitochondrial dysfunction, caspase-3 activation and degradation of FTase/GGTase α-subunit. Potential significance of these findings in the context of protein prenylation and β-cell survival are discussed.
Daleep K Arora; Abiy M Mohammed; Anjaneyulu Kowluru
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  Apoptosis : an international journal on programmed cell death     Volume:  18     ISSN:  1573-675X     ISO Abbreviation:  Apoptosis     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-14     Completed Date:  2013-10-21     Revised Date:  2014-01-09    
Medline Journal Info:
Nlm Unique ID:  9712129     Medline TA:  Apoptosis     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1-8     Citation Subset:  IM    
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MeSH Terms
Alkyl and Aryl Transferases / metabolism*
Caspase 3 / metabolism*
Caspase Inhibitors / pharmacology
Cell Survival / drug effects
Cells, Cultured
Etoposide / antagonists & inhibitors*,  pharmacology
Farnesyltranstransferase / metabolism*
Insulin-Secreting Cells / drug effects,  metabolism*
Nifedipine / pharmacology*
Oligopeptides / pharmacology
Protein Prenylation / drug effects
Rats, Sprague-Dawley
Grant Support
Reg. No./Substance:
0/Caspase Inhibitors; 0/Oligopeptides; 0/benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; 6PLQ3CP4P3/Etoposide; EC 2.5.-/Alkyl and Aryl Transferases; EC 2.5.1.-/geranylgeranyltransferase type-I; EC; EC 3.4.22.-/Caspase 3; I9ZF7L6G2L/Nifedipine

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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