Apoptosis

, Volume 11, Issue 10, pp 1801–1811 | Cite as

PPARγ is a key target of butyrate-induced caspase-3 activation in the colorectal cancer cell line Caco-2

  • Markus Schwab
  • Veerle Reynders
  • Sandra Ulrich
  • Nadine Zahn
  • Jürgen Stein
  • Oliver Schröder
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Abstract

Background: Butyrate, a potent histone deacetylase inhibitor, belongs to a promising new class of antineoplastic agents with the capacity to induce apoptosis of cancer cells. However, the underlying mechanisms of action have yet not been elucidated. Aim: To further investigate the molecular events involved in butyrate-induced caspase-3 activation in Caco-2 wild-type, empty-vector and dominant-negative PPARγ mutant cells along the signalling pathway. In this context, the involvement and up-regulation of PPARγ was examined. Results: Stimulation of cells with butyrate resulted in increased expression of PPARγ mRNA, protein, and activity as well as phospho-p38 MAPK protein expression and caspase-3 activity. Arsenite, a direct stimulator of p38 MAPK, also led to an increased PPARγ expression, thereby mimicking the effects of butyrate. In contrast, butyrate-mediated up-regulation of PPARγ was counteracted by co-incubation with the p38 MAPK inhibitor SB203580. Treatment of cells with butyrate resulted in both increased caspase-8 and -9 activity and reduced expression of XIAP and survivin. However, butyrate-mediated effects on these apoptosis-regulatory proteins leading to caspase-3 activation were almost completely abolished in Caco-2 dominant-negative PPARγ mutant cells. Conclusions: Our data clearly unveil PPARγ as a key target in the butyrate-induced signalling cascade leading to apoptosis via caspase-3 in Caco-2 cells.

Keywords

Apoptosis Butyrate Caspase-3 p38 MAPK PPARγ 

Abbreviations

DFF

DNA Fragmentation Factor

DMEM

Dulbecco’s modified Eagle’s medium

DMSO

Dimethyl sulfoxide

ECACC

European Collection of cell cultures

EGF

Epithelial growth factor

ERK

Extracellular signal-regulated kinase

FCS

Foetal calf serum

FLIP

FLICE-inhibitory protein

HDAC

Histone deacetylase

IAP

Inhibitor of apoptosis protein

JNK

cJun N-terminal kinase

LDH

Lactate dehydrogenase

MAPK

Mitogen-activated protein kinase

PARP

Poly(ADP-ribose) Polymerase

PBS

Phosphate buffered saline

PKC-δ

Protein kinase C-δ

PPARγ

Peroxisome proliferator-activated receptor γ

SCFA

Short chain fatty acid

STAT3

Signal transducer and activator of transcription-3

TBS-T

Tris-buffered saline containing 0.05% Tween 20

TNF

Tumor necrosis factor

XIAP

X linked inhibitor of apoptosis

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Copyright information

© Springer Science + Business Media, LLC 2006

Authors and Affiliations

  • Markus Schwab
    • 1
  • Veerle Reynders
    • 1
  • Sandra Ulrich
    • 1
  • Nadine Zahn
    • 1
  • Jürgen Stein
    • 1
  • Oliver Schröder
    • 1
  1. 1.First Department of Medicine-ZAFESJohann Wolfgang Goethe-University FrankfurtFrankfurt am MainGermany

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