Correction to: Androgen receptor regulates expression of skeletal muscle-specific proteins and muscle cell types.

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Androgen receptor regulates expression of skeletal muscle-specific proteins and muscle cell types.

C2C12 myoblasts expressing the androgen receptor (AR) were used to analyze the role of androgen-AR signaling pathway in skeletal muscle development. Marked up-regulation of AR expression was observed in differentiated myotubes. A nuclear run-on transcription assay demonstrated that transcription of the AR gene is increased during skeletal muscle cell differentiation. Regulation of skeletal muscle-specific protein expression by the androgen-AR signaling pathway was further analyzed using quadriceps skeletal muscle from wild-type (WT) and AR knock-out (ARKO) male mice. A histological analysis of quadriceps skeletal muscle indicates no morphological differences between ARKO and WT mice. However, the androgen-AR signaling pathway increases expression of slow-twitch-specific skeletal muscle proteins and downregulates fast-twitch-specific skeletal muscle proteins, resulting in an increase of slow-twitch muscle fiber type cells in quadriceps muscle.

Interruption of nuclear factor kappaB signaling by the androgen receptor facilitates 12-O-tetradecanoylphorbolacetate-induced apoptosis in androgen-sensitive prostate cancer LNCaP cells.

12-O-tetradecanoylphorbolacetate (TPA) influences proliferation, differentiation, and apoptosis in a variety of cells including prostate cancer cells. Here, we show that androgen treatment potentiates TPA-induced apoptosis in androgen-sensitive prostate cancer LNCaP cells but not in androgen-independent prostate cancer cell lines DU145 and PC-3. The use of the antiandrogen bicalutamide (Casodex) rescued LNCaP cells from 5-alpha-dihydrotestosterone (DHT)/TPA-induced apoptosis, suggesting that DHT/TPA-induced apoptosis is mediated by androgen/androgen receptor (AR). In addition, a caspase-3 inhibitor (Ac-DEVD-CHO) reduced the level of apoptosis, suggesting that DHT/TPA-mediated apoptosis occurs through a caspase-3-dependent pathway. A functional reporter assay using nuclear factor (NF) kappaB-luciferase and an electromobility gel shift assay showed that DHT suppressed NFkappaB activity. In addition, apoptosis mediated by combined DHT/TPA treatment was abrogated by overexpression of the NFkappaB subunit p65 in LNCaP-p65 cells, suggesting that NFkappaB may play an important role in regulating the effects of androgen/AR and TPA on apoptosis. Furthermore, use of the c-Jun N-terminal kinase (JNK) inhibitor SB202190 showed that the combination of DHT/TPA increased JNK activation in LNCaP cells but not in LNCaP-p65 cells, demonstrating that NFkappaB may be able to suppress JNK activity. These results indicate that androgen/AR facilitates TPA-induced apoptosis by interruption of the NFkappaB signaling pathway, leading to activation of JNK in LNCaP cells. These data describe a signaling pathway that could potentially be useful in proposed therapeutic treatment strategies exploiting combinations of different agents that control apoptosis in prostate tumors.