Cyclosporine A induces apoptotic and autophagic cell death in rat pituitary GH3 cells

Hansung Kim, Seung Il Choi, Eui Bae Jeung, Yeong Min Yoo

Research output: Contribution to journalArticle

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Abstract

Cyclosporine A (CsA) is a powerful immunosuppressive drug with side effects including the development of chronic nephrotoxicity. In this study, we investigated CsA treatment induced apoptotic and autophagic cell death in pituitary GH3 cells. CsA treatment (0.1 to 10 μM) decreased survival of GH3 cells in a dose-dependent manner. Cell viability decreased significantly with increasing CsA concentrations largely due to an increase in apoptosis, while cell death rates due to autophagy altered only slightly. Several molecular and morphological features correlated with cell death through these distinct pathways. At concentrations ranging from 1.0 to 10 μM, CsA induced a dose-dependent increase in expression of the autophagy markers LC3-I and LC3-II. Immunofluorescence staining revealed markedly increased levels of both LC3 and lysosomal-associated membrane protein 2 (Lamp2), indicating increases in autophagosomes. At the same CsA doses, apoptotic cell death was apparent as indicated by nuclear and DNA fragmentation and increased p53 expression. In apoptotic or autophagic cells, p-ERK levels were highest at 1.0 μM CsA compared to control or other doses. In contrast, Bax levels in both types of cell death were increased in a dose-dependent manner, while Bcl-2 levels showed dose-dependent augmentation in autophagy and were decreased in apoptosis. Manganese superoxide dismutase (Mn-SOD) showed a similar dose-dependent reduction in cells undergoing apoptosis, while levels of the intracellular calcium ion exchange maker calbindin-D9k were decreased in apoptosis (1.0 to 5 μM CsA), but unchanged in autophagy. In conclusion, these results suggest that CsA induction of apoptotic or autophagic cell death in rat pituitary GH3 cells depends on the relative expression of factors and correlates with Bcl-2 and Mn-SOD levels.

Original languageEnglish
Article numbere108981
JournalPLoS One
Volume9
Issue number10
DOIs
Publication statusPublished - 2014 Oct 9

Fingerprint

cyclosporine
autophagy
Autophagy
Cell death
Cyclosporine
Rats
rats
dosage
cell death
Cell Death
cells
apoptosis
Apoptosis
Lysosomal-Associated Membrane Protein 2
Superoxide Dismutase
cell viability
manganese
Cell Survival
superoxide dismutase
calbindin

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Kim, Hansung ; Choi, Seung Il ; Jeung, Eui Bae ; Yoo, Yeong Min. / Cyclosporine A induces apoptotic and autophagic cell death in rat pituitary GH3 cells. In: PLoS One. 2014 ; Vol. 9, No. 10.
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Cyclosporine A induces apoptotic and autophagic cell death in rat pituitary GH3 cells. / Kim, Hansung; Choi, Seung Il; Jeung, Eui Bae; Yoo, Yeong Min.

In: PLoS One, Vol. 9, No. 10, e108981, 09.10.2014.

Research output: Contribution to journalArticle

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