Inhibition of Src tyrosine kinase stimulates adrenal androgen production

R. Sirianni, B. R. Carr, S. Andò, W. E. Rainey

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

A unique characteristic of the primate adrenal is the ability to produce 19-carbon steroids, often called the adrenal androgens. Although it is clear that the major human adrenal androgens, dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEA-S), are produced almost solely in the adrenal reticularis, the mechanisms regulating production are poorly understood. Herein, we tested the hypothesis that the Src family of tyrosine kinases are involved in the regulation of adrenal androgen production. The NCI-H295R human adrenal cell line and primary human adrenal cells in culture were used to study adrenal androgen production and expression of enzymes involved in steroidogenesis. To examine the role of Src tyrosine kinase, cells were treated with PP2, a specific Src inhibitor. Alternatively, adrenal cells were transfected with an expression vector containing a dominant-negative form of Src. PP2 treatment inhibited basal cortisol production while significantly increasing the production of DHEA and DHEA-S (together referred to as DHEA(S)) in both adrenal cell models. The effect of PP2 on steroidogenesis occurred along with a rapid induction of steroidogenic acute regulatory (StAR) protein synthesis as revealed by Western analysis. Treatment with PP2 also increased mRNA levels for StAR, and cholesterol side-chain cleavage (CYP11A) and 17α-hydroxylase/17,20-lyase (CYP17) enzymes. Treatment of adrenal cells with the cAMP agonist dibutyryladenosine cyclic monophosphate (dbcAMP), stimulated the production of cortisol and DHEA(S). However, treatment of adrenal cells with a combination of PP2 and dbcAMP enhanced the production of DHEA(S) while inhibiting cortisol production. During dbcAMP treatment PP2 was able to augment the expression of CYP17 and to inhibit the induction of 3β-hydroxysteroid dehydrogenase type 2 (HSD3B2) levels. Increasing the CYP17 to HSD3B2 ratio is likely to promote the use of steroid precursors for the production of DHEA(S) and not for cortisol. Taken together these data suggest that the inhibition of Src tyrosine kinases causes adrenal cells to adopt a reticularis phenotype both by the production of DHEA(S) and by the steroidogenic enzymes expressed.

Original languageEnglish (US)
Pages (from-to)287-299
Number of pages13
JournalJournal of Molecular Endocrinology
Volume30
Issue number3
DOIs
StatePublished - Jun 2003

Fingerprint

Dehydroepiandrosterone
src-Family Kinases
Androgens
Steroid 17-alpha-Hydroxylase
Hydrocortisone
Mixed Function Oxygenases
Enzymes
3-Hydroxysteroid Dehydrogenases
Steroids
Zona Reticularis
Dehydroepiandrosterone Sulfate
Primates
Carbon
Cell Culture Techniques
Cholesterol
Phenotype
Cell Line
Messenger RNA

ASJC Scopus subject areas

  • Endocrinology

Cite this

Inhibition of Src tyrosine kinase stimulates adrenal androgen production. / Sirianni, R.; Carr, B. R.; Andò, S.; Rainey, W. E.

In: Journal of Molecular Endocrinology, Vol. 30, No. 3, 06.2003, p. 287-299.

Research output: Contribution to journalArticle

Sirianni, R. ; Carr, B. R. ; Andò, S. ; Rainey, W. E. / Inhibition of Src tyrosine kinase stimulates adrenal androgen production. In: Journal of Molecular Endocrinology. 2003 ; Vol. 30, No. 3. pp. 287-299.
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