title: Anthraquinone emodin inhibits human cancer cell invasiveness by antagonizing P2X7 receptors.
abstract: 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 µM 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 µM emodin, respectively. Emodin specifically inhibited P2X7R-mediated currents with an IC50 of 3 µM 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 µM 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 µM emodin. Taken together, these results provide consistent evidence to indicate that emodin inhibits human cancer cell invasiveness by specifically antagonizing the P2X7R.
authors.affiliation: Inserm U1069 Nutrition, Growth and Cancer, Université François-Rabelais de Tours, 10 Boulevard Tonnellé, 37032 Tours, France.
authors.forename: Bilel
authors.initials: B
authors.lastname: Jelassi
authors.forename: Monique
authors.initials: M
authors.lastname: Anchelin
authors.forename: Julie
authors.initials: J
authors.lastname: Chamouton
authors.forename: María Luisa
authors.initials: ML
authors.lastname: Cayuela
authors.forename: Lucie
authors.initials: L
authors.lastname: Clarysse
authors.forename: Junying
authors.initials: J
authors.lastname: Li
authors.forename: Jacques
authors.initials: J
authors.lastname: Goré
authors.forename: Lin-Hua
authors.initials: LH
authors.lastname: Jiang
authors.forename: Sébastien
authors.initials: S
authors.lastname: Roger
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D048430:Cell Shape / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004642:Emodin / Q000494:pharmacology*; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D023421:Models, Animal; D009361:Neoplasm Invasiveness / Q000473:pathology / Q000517:prevention & control*; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000473:pathology; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism*; D012250:Rheum / Q000737:chemistry; D014162:Transfection; D015027:Zebrafish / Q000196:embryology / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D058920:Purinergic P2X Receptor Antagonists; D034741:RNA, Small Interfering; D058486:Receptors, Purinergic P2X7; D000255:Adenosine Triphosphate; D004642:Emodin; D002118:Calcium