Insulin-like growth factor I enhances the expression of aromatase P450 by inhibiting autophagy

23Citations
Citations of this article
17Readers
Mendeley users who have this article in their library.

Abstract

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. Copyright © 2010 by The Endocrine Society.

Cite

CITATION STYLE

APA

Zhang, B., Shozu, M., Okada, M., Ishikawa, H., Kasai, T., Murakami, K., … Inoue, M. (2010). Insulin-like growth factor I enhances the expression of aromatase P450 by inhibiting autophagy. Endocrinology, 151(10), 4949–4958. https://doi.org/10.1210/en.2010-0294

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Save time finding and organizing research with Mendeley

Sign up for free