Caspase-4 is essential for saikosaponin a-induced apoptosis acting upstream of caspase-2 and γ-H2AX in colon cancer cells

Su Jin Kang, Young Joon Lee, Sung Gu Kang, Soyoung Cho, Wonsuck Yoon, Ji Hong Lim, Sang Hyun Min, Tae Ho Lee, Byeong Mo Kim

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)

Abstract

Saikosaponin a (SSa), a bioactive phytochemical from Bupleurum, triggers sequential caspase-2 and caspase-8 activation, and thereby induces caspase-mediated apoptosis in human colon carcinoma (HCC) cells. However, the upstream mechanism of caspase-2 activation remains unknown. Therefore, we investigated the signaling mechanisms underlying SSa-induced caspase activation and apoptosis in HCC cells. SSa treatment triggered marked antitumor effects, especially in HCC cells, in a cell culture model and a mouse xenograft model. SSa also induced the activation of several endoplasmic reticulum (ER) stress signals. Specifically, caspase-4, a critical regulator of ER stress-induced apoptosis, was activated significantly after SSa treatment. Mechanistically, selective inhibition of caspase-4 suppressed SSainduced apoptosis, colony inhibition, and the activation of caspase-3, -8, and -2, but not vice versa. Consistent with the important role of caspase-2 in the DNA damage response, SSa induced DNA damage, as evidenced by a cytokinesis-block micronucleus assay, single-cell gel electrophoresis, and an increase in the levels of γ-H2AX, a DNA damage marker. Moreover, inhibition of caspase-4 activation inhibited SSa-induced histone H2AX phosphorylation. Taken together, these results suggest that caspase-4 is an upstream regulator of SSa-induced DNA damage and caspase activation in HCC cells. Given that SSa-induced apoptosis appeared to be specific to certain cell types including HCC cells, SSa may be a promising cancer therapy agent in certain types of cancer.

Original languageEnglish
Pages (from-to)100433-100448
Number of pages16
JournalOncotarget
Volume8
Issue number59
DOIs
Publication statusPublished - 2017
Externally publishedYes

Keywords

  • Caspase-4
  • DNA damage
  • Endoplasmic reticulum (ER) stress
  • Human colon carcinoma (HCC)
  • Saikosaponin a (SSa)

ASJC Scopus subject areas

  • Oncology

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