Estrogens and human papilloma virus oncogenes regulate human Ether-à-go-go-1 potassium channel expression

Lorenza Díaz, Irais Ceja-Ochoa, Iván Restrepo-Angulo, Fernando Larrea, Euclides Avila-Chávez, Rocío García-Becerra, Elizabeth Borja-Cacho, David Barrera, Elías Ahumada, Patricio Gariglio, Elizabeth Alvarez-Rios, Rodolfo Ocadiz-Delgado, Enrique Garcia-Villa, Elizabeth Hernández-Gallegos, Ignacio Camacho-Arroyo, Angélica Morales, David Ordaz-Rosado, Ethel García-Latorre, Juan Escamilla, Luz Carmen Sánchez-PeñaMilena Saqui-Salces, Armando Gamboa-Dominguez, Eunice Vera, Marisela Uribe-Ramírez, Janet Murbartián, Cindy Sharon Ortiz, Claudia Rivera-Guevara, Andrea De Vizcaya-Ruiz, Javier Camacho

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

Abstract

Ether-à-go-go-1 (Eag1) potassium channels are potential tools for detection and therapy of numerous cancers. Here, we show human Eagl (hEag1) regulation by cancer-associated factors. We studied hEag1 gene expression and its regulation by estradiol, antiestrogens, and human papillomavirus (HPV) oncogenes (E6/E7). Primary cultures from normal placentas and cervical cancer tissues; tumor cell lines from cervix, choriocarcinoma, keratinocytes, and lung; and normal cell lines from vascular endothelium, keratinocytes, and lung were used. Reverse transcription-PCR (RT-PCR) experiments and Southern blot analysis showed Eag1 expression in all of the cancer cell types, normal trophoblasts, and vascular endothelium, in contrast to normal keratinocytes and lung cells. Estradiol and antiestrogens regulated Eag1 in a cell type-dependent manner. Real-time RT-PCR experiments in HeLa cells showed that Eag1 estrogenic regulation was strongly associated with the expression of estrogen receptor-α. Eagl protein was detected by monoclonal antibodies in normal placenta and placental blood vessels. Patch-clamp recordings in normal trophoblasts treated with estradiol exhibited potassium currents resembling Eagl channel activity. Eag1 gene expression in keratinocytes depended either on cellular immortalization or the presence of HPV oncogenes. Eag1 protein was found in keratinocytes transfected with E6/E7 HPV oncogenes. Cell proliferation of E6/E7 keratinocytes was decreased by Eagl antibodies inhibiting channel activity and by the nonspecific Eagl inhibitors imipramine and astemizole; the latter also increased apoptosis. Our results propose novel oncogenic mechanisms of estrogen/ antiestrogen use and HPV infection. We also suggest Eagl as an early indicator of cell proliferation leading to malignancies and a therapeutic target at early stages of cellular hyperproliferation.

Original languageEnglish (US)
Pages (from-to)3300-3307
Number of pages8
JournalCancer Research
Volume69
Issue number8
DOIs
StatePublished - Apr 15 2009

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