Inhibition of the Androgen Receptor by Antisense Oligonucleotides Regulates the Biological Activity of Androgens in SZ95 Sebocytes

Abstract

One novel strategy for the blockade of the androgen receptor could be the selective inhibition of androgen receptor by antisense oligonucleotides or small interfering RNA molecules. Here we describe the down regulation of the androgen receptor in cultured human SZ95 sebocytes with antisense oligonucleotides modified with phosphorothioates and 2'- O-methylribosyl residues. The ability of antisense oligonucleotides to cross the cellular membrane was enhanced by establishing a transient transfection system based on cationic lipid vesicles. Both antisense oligonucleotide types administered caused assumedly translational arrest. Dose-dependent inhibition of androgen receptor protein expression was observed after SZ95 sebocyte transfection with modified phosphorothioate oligonucleotides and modified 2'- O-methylribonucleotides which were directed against the translational start of the androgen receptor mRNA. The strongest transient inhibition of androgen receptor expression was detected after 14 hours with 1.0 muM antisense 2'- O-methylribonucleotides (88+/-1.3%, p<0.001). With longer recovery times than 24 hours, androgen receptor protein expression returned to the native control levels. Inhibition of the expression of androgen receptor by antisense oligonucleotides, reduced the enhanced proliferation of SZ95 sebocytes challenged by testosterone and 5alpha-dihydrotestosterone. This administration opens new therapeutic possibilities in androgen-associated skin diseases, since we could also show androgen inhibition with these antisense oligonucleotides in a reconstituted human epidermis model (Horm Metab Res 2007; 39:157-165).

Beyond acne: Current aspects of sebaceous gland biology and function

“…5α-DHT binds to the AR with greater affinity than testosterone and the 5α-DHT/androgen receptor complex appears to be more stable and, therefore, more effective. AR is stabilized and upregulated by ligand binding; its downregulation reduces sebocyte proliferation [83,84]. A dosedependent induction of sebocyte proliferation by testosterone treatment and no effect on lipid stimulation has been demonstrated [15].…”

“…Testosterone and 5α-DHT regulate SG function through binding to the nuclear androgen receptor (AR) [83]. AR is a member of the steroid superfamily of ligand-dependent transcription factors.…”

The Brain of the Skin: Sebaceous Gland

“…The steroid receptor family is represented in human sebocytes by the androgen receptor (AR) and the progesterone receptor (PR), which are mostly expressed in basal and early differentiated sebocytes Fritsch et al 2001;Fimmel et al 2007). …”

Die Talgdrüse

“…Der AR wird stabilisiert und hochreguliert durch Ligandenbindung, seine Downregulation reduziert die Sebozytenproliferation [60]. Fünf intrazelluläre Enzyme, die alle in Sebozyten exprimiert werden [21], sind an der Aktivierung beteiligtvor der Bindung an den AR -und an der Inaktivierung von Androgenen.…”