TY - JOUR
T1 - Estrogens and human papilloma virus oncogenes regulate human Ether-à-go-go-1 potassium channel expression
AU - Díaz, Lorenza
AU - Ceja-Ochoa, Irais
AU - Restrepo-Angulo, Iván
AU - Larrea, Fernando
AU - Avila-Chávez, Euclides
AU - García-Becerra, Rocío
AU - Borja-Cacho, Elizabeth
AU - Barrera, David
AU - Ahumada, Elías
AU - Gariglio, Patricio
AU - Alvarez-Rios, Elizabeth
AU - Ocadiz-Delgado, Rodolfo
AU - Garcia-Villa, Enrique
AU - Hernández-Gallegos, Elizabeth
AU - Camacho-Arroyo, Ignacio
AU - Morales, Angélica
AU - Ordaz-Rosado, David
AU - García-Latorre, Ethel
AU - Escamilla, Juan
AU - Sánchez-Peña, Luz Carmen
AU - Saqui-Salces, Milena
AU - Gamboa-Dominguez, Armando
AU - Vera, Eunice
AU - Uribe-Ramírez, Marisela
AU - Murbartián, Janet
AU - Ortiz, Cindy Sharon
AU - Rivera-Guevara, Claudia
AU - Vizcaya-Ruiz, Andrea De
AU - Camacho, Javier
PY - 2009/4/15
Y1 - 2009/4/15
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=65949083785&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-08-2036
DO - 10.1158/0008-5472.CAN-08-2036
M3 - Article
C2 - 19351862
AN - SCOPUS:65949083785
SN - 0008-5472
VL - 69
SP - 3300
EP - 3307
JO - Cancer Research
JF - Cancer Research
IS - 8
ER -