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 journalArticle

14 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 Jan 1

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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  • Cite this

    Kang, S. J., Lee, Y. J., Kang, S-G., Cho, S., Yoon, W., Lim, J. H., Min, S. H., Lee, T. H., & Kim, B. M. (2017). Caspase-4 is essential for saikosaponin a-induced apoptosis acting upstream of caspase-2 and γ-H2AX in colon cancer cells. Oncotarget, 8(59), 100433-100448. https://doi.org/10.18632/oncotarget.22247