Expression of endothelin 1 and endothelin A receptor in HPV-associated cervical carcinoma: new potential targets for anticancer therapy.
Human papillomaviruses (HPV) are associated with cervical cancer and interact with growth factors that may enhance malignant transformation of cervical carcinoma cells. Endothelin-1 (ET-1) is released from HPV transfected keratinocytes and induces increased growth response in these cell lines in comparison with normal cells. In the present study several cervical carcinoma cell lines have been analyzed to investigate the expression of ET-1 and its receptors as well as their involvement in tumor growth. All HPV-positive cancer cells secreted ET-1 and expressed mRNA for ET-1 and its receptors, whereas a HPV-negative carcinoma cell line expressed only the ETBR mRNA and didn't secrete ET-1. Binding studies showed that HPV-associated cells expressed an increased number of functional ETAR. ET-1 stimulated a marked dose-dependent increase in [3H]-thymidine incorporation with respect to the normal cells whereas ET-3 and ETBR agonists had no effect. In HPV-positive cancer cells, a specific antagonist of ETAR inhibited the proliferation induced by ET-1 and substantially reduced the basal growth rate of unstimulated cervical tumor cells, whereas the ETBR antagonist had no effect. These results demonstrate that ET-1 participates in the progression of neoplastic growth in HPV-associated carcinoma, in which ETAR are increased and could be targeted for antitumor therapy.
Venuti
A
A
Laboratories of Virology, Regina Elena Cancer Institue, 00158 Rome, Italy. venuti@ifo.it
Salani
D
D
Manni
V
V
Poggiali
F
F
Bagnato
A
A
D000970:Antineoplastic Agents / Q000627:therapeutic use; D001667:Binding, Competitive / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009842:Oligopeptides / Q000494:pharmacology; D027383:Papillomaviridae; D030361:Papillomavirus Infections / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011863:Radioimmunoassay; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014412:Tumor Virus Infections / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000821:virology; D014757:Viper Venoms / Q000494:pharmacology
D000970:Antineoplastic Agents; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; D014757:Viper Venoms; C057354:sarafotoxins s6; C086539:BQ 788; C072247:cyclo(Trp-Asp-Pro-Val-Leu)