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1.
Endocrinology ; 151(10): 4949-58, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20668023

RESUMO

Aromatase, a key enzyme of estrogen biosynthesis, is transcriptionally regulated by many growth factors. IGF-I enhances aromatase activity in a variety of cells, but the mechanism of action has not been determined. We herein report our finding of a novel mechanism of action for IGF-I. IGF-I enhanced the dexamethasone (DEX)-induced aromatase activity by 30% in serum-starved THP-1 cells. The increase was associated with a corresponding increase in the level of aromatase protein but not with any change in the mRNA level. Metabolic labeling experiments revealed that IGF-I inhibited the degradation of aromatase. We identified pepstatin A as the most effective inhibitor of aromatase degradation by in vitro assay. Using a nontoxic concentration of pepstatin A, we examined IGF-I's action on aromatase distribution in microsomes and lysosomes. In the presence of pepstatin A, DEX caused an increase in the amount of aromatase in both microsomes and lysosomes, and IGF-I attenuated the DEX-induced accumulation of aromatase in lysosomes and, conversely, enhanced its accumulation in the microsomes. The addition of serum abolished the IGF-I-induced changes. The transport from microsome to lysosome was fluorescently traced in cells using a recombinant aromatase. IGF-I selectively reduced the aromatase signal in the lysosomes. Finally, we observed that IGF-I enhanced the aromatase activity by 50% as early as 1 h after treatment; furthermore, rapamycin, an enhancer of autophagy, completely negated the effect of IGF-I on the enzyme. These results indicate that IGF-I enhances aromatase by the inhibition of autophagy.


Assuntos
Aromatase/genética , Autofagia/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/farmacologia , Aromatase/metabolismo , Autofagia/genética , Linhagem Celular Tumoral , Dexametasona/farmacologia , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Ativação Enzimática/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Humanos , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Pepstatinas/farmacologia , Inibidores de Proteases/farmacologia , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Estabilidade Proteica/efeitos dos fármacos , RNA Mensageiro/metabolismo , Regulação para Cima/efeitos dos fármacos
2.
Clin Cancer Res ; 11(6): 2188-94, 2005 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-15788666

RESUMO

PURPOSE AND EXPERIMENTAL DESIGN: To assess the prognostic significance of intratumoral aromatase in endometrioid endometrial cancer, sections from 55 patients with endometrial cancer were evaluated for expression of aromatase using immunohistochemistry, and the correlation between aromatase expression and clinicopathologic parameters were analyzed. RESULTS: Immunohistochemical staining for aromatase was positive for 32 (58%), 20 (36%), and 19 (34%) patients in cancer epithelial cells, stromal cells, and myometrial cells around the flank invasion, respectively. In situ hybridization also detected aromatase mRNA in all three types of cells. RT-PCR analysis revealed that aromatase mRNA was 2.5 +/- 1.0 amol/mug total RNA (mean +/- SE; n = 7) in tumor tissue. Western blot analysis detected the expected aromatase protein size of 58 kDa in cancer tissues more abundantly than in cancer-free endometrium (n = 3). The immunoreactivity in stromal cells correlated positively with advanced surgical stage and poor survival. Survival analysis revealed that the immunoreactivity of stromal cells was a significant prognostic factor, independent of histologic grade, muscular invasion, and lymph node metastasis, but dependent on surgical stage. By contrast, the immunoreactivity of aromatase both in cancer epithelial cells and myometrial cells did not correlate with prognosis. CONCLUSIONS: To the best of our knowledge, this is the first evidence associating intratumoral aromatase expression in stromal cells and poor survival in endometrioid endometrial cancer. This positive linkage indicates that local expression of aromatase plays a role in tumor progression through the formation of in situ estrogens. In situ expression of aromatase may offer a potential target for management of endometrial cancers.


Assuntos
Aromatase/metabolismo , Carcinoma Endometrioide/diagnóstico , Carcinoma Endometrioide/enzimologia , Células Estromais/enzimologia , Aromatase/genética , Progressão da Doença , Endométrio/enzimologia , Células Epiteliais/enzimologia , Células Epiteliais/patologia , Feminino , Humanos , Hibridização In Situ , Metástase Linfática/patologia , Pessoa de Meia-Idade , Miométrio/enzimologia , Miométrio/patologia , Invasividade Neoplásica/patologia , Prognóstico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxa de Sobrevida
3.
Semin Reprod Med ; 22(1): 51-60, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15083381

RESUMO

In leiomyoma of the uterus, both aromatase and 17beta-hydroxysteroid dehydrogenase (17beta-HSD) type I are overexpressed compared with myometrium. This suggests that leiomyoma cells convert circulating androstenedione into estrone (via aromatase), then into the active form of estrogen, estradiol (via 17beta-HSD type I). In vitro experiments and several clinical findings support the notion that in situ estrogen plays a role in leiomyoma growth under hypoestrogenemic conditions, such as natural menopause and therapy with gonadotropin-releasing hormone (GnRH) agonists. GnRH agonists abolish estrogen production both in situ in leiomyoma and in the ovary, leading to quick and profound regression of the leiomyoma. Aromatase inhibitors also inhibit estrogen synthesis in both leiomyoma and the ovary and may be used therapeutically. Certain doses of competitive aromatase inhibitors would completely inhibit estrogen production in leiomyoma, whereas ovarian production of estrogen would continue at reduced levels. This may lead to advantageous therapeutic conditions in which leiomyoma regresses without adverse symptoms related to estrogen depletion because levels of ovarian estrogen would be insufficient to support leiomyoma growth but sufficient to prevent symptoms associated with deficiency. This article discusses the potential uses of aromatase inhibitors.


Assuntos
Aromatase/metabolismo , Leiomioma/enzimologia , Neoplasias Uterinas/enzimologia , Aromatase/genética , Inibidores da Aromatase , Inibidores Enzimáticos/uso terapêutico , Estrogênios/biossíntese , Feminino , Hormônio Liberador de Gonadotropina/agonistas , Hormônio Liberador de Gonadotropina/uso terapêutico , Humanos , Leiomioma/tratamento farmacológico , Leiomioma/metabolismo , Neoplasias Uterinas/tratamento farmacológico , Neoplasias Uterinas/metabolismo
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