Caspase-4 is essential for saikosaponin a-induced apoptosis acting upstream of caspase-2 and gamma-H2AX in colon cancer cells
- Authors
- Kang, Su Jin; Lee, Young Joon; Kang, Sung Gu; Cho, Soyoung; Yoon, Wonsuck; Lim, Ji Hong; Min, Sang-Hyun; Lee, Tae Ho; Kim, Byeong Mo
- Issue Date
- 21-11월-2017
- Publisher
- IMPACT JOURNALS LLC
- Keywords
- saikosaponin a (SSa); human colon carcinoma (HCC); endoplasmic reticulum (ER) stress; caspase-4; DNA damage
- Citation
- ONCOTARGET, v.8, no.59, pp.100433 - 100448
- Indexed
- SCIE
SCOPUS
- Journal Title
- ONCOTARGET
- Volume
- 8
- Number
- 59
- Start Page
- 100433
- End Page
- 100448
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/81521
- DOI
- 10.18632/oncotarget.22247
- ISSN
- 1949-2553
- 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 SSa-induced 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 gamma-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.
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Collections - College of Medicine > Department of Medical Science > 1. Journal Articles
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