Insulin-Like Growth Factor I Enhances the Expression of Aromatase P450 by Inhibiting Autophagy

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.

Effects of Fibroblast Growth Factor 9 (FGF9) on Steroidogenesis and Gene Expression and Control of FGF9 mRNA in Bovine Granulosa Cells

“…Another explanation for lack of effect of FGF9 on CYP19A1 mRNA expression despite the inhibition of E2 would be that FGF9 may be acting on aromatase protein in a posttranslational manner. In serum-starved human monocyte leukemia cells, IGF-I stabilizes aromatase protein via a posttranscriptional mechanism increasing aromatase by inhibiting autophagy, which is a degradation pathway for the disposal of cellular components (69). If FGF9 blocks the IGF-I-induced inhibition of aromatase autophagy, increased turnover of aromatase would occur and lead to less E2 produced.…”

Alcohol Exposure In Utero Leads to Enhanced Prepubertal Mammary Development and Alterations in Mammary IGF and Estradiol Systems

“…The finding of increased aromatase expression is significant given the multiple mechanisms by which E2 may enhance cell proliferation, including both classical genomic effects as well as more recently recognized non-genomic effects that include cross-talk with the IGFR system [11,36,37]. While the mechanism responsible for the increase in aromatase expression is unclear, it is interesting that IGF-I enhances aromatase expression in multiple cell types [38,39]. Therefore, it is possible that the increase in IGF-I activity is related to the increase in aromatase expression.…”

Biological Basis of Alcohol-Induced Cancer

“…Nonetheless, retinoids could be potential components of innovative and rational therapeutic combinations for breast cancer. Yet, it is important to evaluate the responsiveness of ER+ tumors to retinoids and whether HER2 expression always plays a negative role in modulating retinoid sensitivity of HER2+/ ER+ mammary tumors, as suggested by some studies [ 98 ].…”

“…Interestingly, IGF-I enhances aromatase activity in a variety of cells although the mechanism is not well understood. Recently, IGF-I was shown to increase aromatase activity by decreasing degradation of aromatase with no corresponding change in mRNA levels [ 98 ]. Therefore both IGF-I and E2 expression may be increased locally in mammary glands of alcohol-exposed offspring, where they may crosstalk to promote mammary proliferation in early development.…”