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Environ Toxicol. 2015 Sep;30(10):1205-15. doi: 10.1002/tox.21992. Epub 2014 Apr 5.

Latex of Euphorbia antiquorum-induced S-phase arrest via active ATM kinase and MAPK pathways in human cervical cancer HeLa cells.

Author information

1
Department of Pharmacology, China Medical University, Taichung, Taiwan.
2
School of Pharmacy, China Medical University, Taichung, Taiwan.
3
Tsuzuki Institute for Traditional Medicine, College of Pharmacy, China Medical University, Taichung, Taiwan.
4
Department of Pharmacology, School of Medicine, Geriatric Research, Education and Clinical Center, VA Medical Center, University of Minnesota, Minneapolis, Minnesota.
5
Department of Clinical Pathology, Cheng Hsin General Hospital, Taipei, 112, Taiwan.
6
Department of Restaurant, Hotel and Institutional Management, Fu-Jen Catholic University, New Taipei, 242, Taiwan.
7
Department of Biological Science and Technology, China Medical University, Taichung, 404, Taiwan.
8
Department of Biotechnology, Asia University, Taichung, 413, Taiwan.

Abstract

Latex of Euphorbia antiquorum (EA) has demonstrated great chemotherapeutic potential for cancer. However, the mechanisms of anti-proliferation of EA on cancer cell remain to be further investigated. The purpose of this study was to explore the influence of EA in human cervical cancer cells. Here, the cell cycle distribution by flow cytometry was examined and the protein expression by the western blotting methods was analyzed. From the cytometric results it was shown that EA-induced S-phase arrest in a concentration manner both in human cervical cancer HeLa and CaSki cells. According the western blot results it was illustrated that EA could downregulate early cyclin E1-Cdk2; and cyclin A-Cdc2 provides a significant additional quantity of S-phase promotion, that in turn promoted the expression of p21(waf1/cip1) and p27(kip1) which were the inhibitors in the complex of cyclin A and Cdc2 that led to cell cycle arrest. Moreover, EA promoted the activation of ataxia telangiectasia mutated (ATM) and check-point kinase-2 (Chk2); however, it negatively regulated the expression of Topoisomerases I and II, Cdc25A, and Cdc25C signaling. Caffeine, an ATM/ATR inhibitor significantly reversed EA downregulation in the levels of Cdc25A. Furthermore, JNK inhibitor SP600125 and p38 MAPK inhibitor SB203580 both could reverse the EA upregulation of the protein of Chk2 level, significantly. This study, therefore, revealed that EA could downregulate topoisomerase, and activate ATM kinase, which then induce parallel Chk 1/2 and MAPK signaling pathways to promote the degradation of Cdc25A to induced S-phase arrest in human cervical cancer HeLa cells.

KEYWORDS:

ATM/ATR; Cdc2; Cdc25C; Chk1/2; EA; cell cycle; cervical cancer; topoisomerase I

PMID:
24706497
DOI:
10.1002/tox.21992
[Indexed for MEDLINE]
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