Apoptosis induction of 2′-hydroxycinnamaldehyde as a proteasome inhibitor is associated with ER stress and mitochondrial perturbation in cancer cells

Su Hyung Hong, Jina Kim, Jung Min Kim, So Young Lee, Dae Seop Shin, Kwang Hee Son, Dong Cho Han, Young Kwan Sung, Byoung Mog Kwon

Research output: Contribution to journalArticlepeer-review

65 Scopus citations

Abstract

2′-Hydroxycinnamaldehyde (HCA), isolated from the stem bark of Cinnamomum cassia, and 2′-benzoyloxycinnamaldehyde (BCA), one of HCA derivatives, have antiproliferative activities on several human cancer cell lines. Our previous study suggested that reactive oxygen species (ROS) and caspase-3 are the major regulators of HCA-induced apoptosis. In the present study, we demonstrated a novel molecular target using in vitro pull-down assay by biotin-labeled HCA (biotin-HCA) in SW620 cells. We analyzed 11 differential spots of 2-dimensional gel prepared with pull-downed proteins by biotin-HCA. Among them, five spots were identified as proteasome subunits. An in vitro 26S proteasome function assay using specific fluorogenic substrates showed that HCA potently inhibits L3-like activity of the proteasome. In addition, HCA showed inhibitory action against chymotrypsin-like, trypsin-like, and PGPH-like activities. DNA microarray showed that HCA induced heat shock family and ER stress-responsive genes, which reflects the accumulation of misfolded proteins by proteasome inhibition. On western blot analysis, it was confirmed that HCA induces glucose-regulated protein, 78 kDa (GRP78) and some representative endoplasmic reticulum (ER) stress-responsive proteins. Furthermore, HCA treatment decreased mitochondrial membrane potential. The effect of HCA on cytochrome c and Bax translocation between cytosol and mitochondrial membrane was clarified using western blot analysis. These results suggest that HCA-induced apoptosis is associated with the inhibition of the proteasome activity that leads in turn to the increase of ER stress and mitochondrial perturbation.

Original languageEnglish
Pages (from-to)557-565
Number of pages9
JournalBiochemical Pharmacology
Volume74
Issue number4
DOIs
StatePublished - 15 Aug 2007

Keywords

  • 2′-hydroxycinnamaldehyde
  • Apoptosis
  • Endoplasmic reticulum
  • Mitochondria
  • Proteasome

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