Endothelin receptor blockade inhibits the growth of human papillomavirus-associated cervical carcinoma.
Human papillomaviruses (HPVs) 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. HPV-positive cancer cells secrete ET-1 and express mRNA for ET-1 and its receptors, whereas HPV-negative carcinoma cell lines express only the ET(B) receptor (ET(B)R) mRNA and do not secrete ET-1. In HPV-positive cancer cells, ET(A)R mediates the ET-1-induced mitogenic effect and sustains the basal growth rate of unstimulated cervical tumour cells. Therefore, ET-1 may be involved in the neoplastic growth of HPV-associated cervical carcinoma, where the increased ET-1 autocrine loop can be targeted for antitumour therapy. In the present work, the action of specific antagonists of ET(A)R (BQ-123 and ABT-627), was analysed in CaSki and C33A cells that are derived from human cervical carcinoma. CaSki cells are HPV-16-positive, produce ET-1 and possess ET(A)R and ET(B)R, whereas the C33A line is HPV-negative, does not secrete ET-1 and has no ET(A)R. In HPV-positive cancer cells ABT-627 strongly inhibited the proliferation induced by ET-1 and substantially reduced the basal growth rate of unstimulated cervical tumour cells, whereas the ET(B)R antagonist had no effect. These results demonstrate that ET-1 participates in the progression of neoplastic growth in HPV-associated carcinoma, in which ET(A)R expression is increased and could be targeted for antitumour therapy. In conclusion, an ET-1 autocrine loop is involved in tumour cell proliferation via ET(A)R, and ABT-627 is effective in controlling proliferation of cervical carcinoma cells.
Laboratory of Virology, Regina Elena Cancer Institute, Via delle Messi d'Oro 156, 00158 Rome, Italy. venuti@ifo.it
Aldo
A
Venuti
Debora
D
Salani
Alessia
A
Cirilli
Paola
P
Simeone
Antonio
A
Muller
Silvio
S
Flamini
Robert
R
Padley
Anna
A
Bagnato
D000077868:Atrasentan; D002455:Cell Division / Q000187:drug effects; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism; D005260:Female; D006801:Humans; D027383:Papillomaviridae; D010456:Peptides, Cyclic / Q000627:therapeutic use*; D011759:Pyrrolidines / Q000627:therapeutic use*; D044022:Receptor, Endothelin A; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000821:virology
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D010456:Peptides, Cyclic; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D000077868:Atrasentan