Latex of Euphorbia antiquorum-induced S-phase arrest via active ATM kinase and MAPK pathways in human cervical cancer HeLa cells.
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.
Department of Pharmacology, China Medical University, Taichung, Taiwan.
Wen-Tsong
WT
Hsieh
School of Pharmacy, China Medical University, Taichung, Taiwan.
Hui-Yi
HY
Lin
Department of Pharmacology, China Medical University, Taichung, Taiwan.
Jou-Hsuan
JH
Chen
Department of Pharmacology, China Medical University, Taichung, Taiwan.
Wen-Chung
WC
Lin
Tsuzuki Institute for Traditional Medicine, College of Pharmacy, China Medical University, Taichung, Taiwan.
Yueh-Hsiung
YH
Kuo
Department of Pharmacology, School of Medicine, Geriatric Research, Education and Clinical Center, VA Medical Center, University of Minnesota, Minneapolis, Minnesota.
W Gibson
WG
Wood
Department of Clinical Pathology, Cheng Hsin General Hospital, Taipei, 112, Taiwan.|Department of Restaurant, Hotel and Institutional Management, Fu-Jen Catholic University, New Taipei, 242, Taiwan.
Hsu-Feng
HF
Lu
Department of Biological Science and Technology, China Medical University, Taichung, 404, Taiwan.|Department of Biotechnology, Asia University, Taichung, 413, Taiwan.
Jing-Gung
JG
Chung
D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D019925:Cyclin A / Q000037:antagonists & inhibitors / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D028481:Euphorbia / Q000737:chemistry* / Q000378:metabolism; D005260:Female; D006367:HeLa Cells; D006801:Humans; D007840:Latex / Q000737:chemistry / Q000633:toxicity*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000473:pathology; D020687:cdc25 Phosphatases / Q000378:metabolism
D019925:Cyclin A; D050759:Cyclin-Dependent Kinase Inhibitor p21; D007840:Latex; D047428:Protein Kinase Inhibitors; D050760:Cyclin-Dependent Kinase Inhibitor p27; D011494:Protein Kinases; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D016203:CDC2 Protein Kinase; D020928:Mitogen-Activated Protein Kinases; C517004:CDC25A protein, human; C517009:CDC25C protein, human; D020687:cdc25 Phosphatases; D004264:DNA Topoisomerases, Type I
ATM/ATR; Cdc2; Cdc25C; Chk1/2; EA; cell cycle; cervical cancer; topoisomerase I