期刊
CARCINOGENESIS
卷 34, 期 7, 页码 1487-1496出版社
OXFORD UNIV PRESS
DOI: 10.1093/carcin/bgt099
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资金
- Ligue Nationale Contre le Cancer - Conseil Scientifique Inter Regional Grand Ouest
- Association CANCEN
- Ministere de la Recherche et des Technologies
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- Region Centre
- Ligue Nationale Contre le Cancer - Comite National
- University of Tours
The adenosine 5'-triphosphate (ATP)-gated Ca-2-permeable channel P2X7 receptor (P2X7R) is strongly upregulated in many tumors and cancer cells, and has an important role in cancer cell invasion associated with metastases. Emodin (1,3,8-trihydroxy-6-methylanthraquinone) is an anthraquinone derivative originally isolated from Rheum officinale Baill known for decades to possess anticancer properties. In this study, we examined the effects of emodin on P2X7R-dependent Ca-2 signaling, extracellular matrix degradation, and in vitro and in vivo cancer cell invasiveness using highly aggressive human cancer cells. Inclusion of emodin at doses 10 M in cell culture had no or very mild effect on the cell viability. ATP elicited increases in intracellular Ca-2 concentration were reduced by 35 and 60% by 1 and 10 M emodin, respectively. Emodin specifically inhibited P2X7R-mediated currents with an IC50 of 3 M and did not inhibit the currents mediated by the other human P2X receptors heterologously expressed in human embryonic kidney (HEK293T) cells. ATP-induced increase in gelatinolytic activity, in cancer cell invasiveness in vitro and in cell morphology changes were prevented by 1 M emodin. Furthermore, such ATP-evoked effects and inhibition by emodin were almost completely ablated in cancer cells transfected with P2X7R-specific small interfering RNA (siRNA) but not with scrambled siRNA. Finally, the in vivo invasiveness of the P2X7R-positive MDA-MB-435s breast cancer cells, assessed using a zebrafish model of micrometastases, was suppressed by 40 and 50% by 1 and 10 M emodin. Taken together, these results provide consistent evidence to indicate that emodin inhibits human cancer cell invasiveness by specifically antagonizing the P2X7R.
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