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Apoptosis

, Volume 18, Issue 1, pp 1–8 | Cite as

Nifedipine prevents etoposide-induced caspase-3 activation, prenyl transferase degradation and loss in cell viability in pancreatic β-cells

  • Daleep K. Arora
  • Abiy M. Mohammed
  • Anjaneyulu KowluruEmail author
Original Paper

Abstract

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.

Keywords

Etoposide Caspase-3 Farnesyl transferase Geranylgeranyl transferase Nifedipine 

Abbreviations

CSP3

Caspase-3

ET

Etoposide

FTase α

Farnesyltransferase α subunit

GGTase α

Geranylgeranyltransferase α subunit

Δ FTase/GGTase

Hydrolytic product of FTase/GGTase α-subunit

MTT

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

Nif

Nifedipine

Notes

Acknowledgments

This research was supported in part by a Merit Review award [to AK; 1BX000469] from the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development Biomedical Laboratory Research and Development], and by the NIH/NIDDK [RO1 DK74921]. AK is also the recipient of a Senior Research Career Scientist Award from the Department of VA. The authors would like to thank Prof. Chris Newgard for INS 832/13 cells. We thank Dr. Wasanthi Subasinghe for excellent technical assistance in these studies.

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Copyright information

© Springer Science+Business Media New York (outside the USA)  2012

Authors and Affiliations

  • Daleep K. Arora
    • 1
    • 2
  • Abiy M. Mohammed
    • 1
    • 2
  • Anjaneyulu Kowluru
    • 1
    • 2
    Email author
  1. 1.Beta-Cell Biochemistry LaboratoryJohn D. Dingell VA Medical CenterDetroitUSA
  2. 2.Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health SciencesWayne State UniversityDetroitUSA

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