Abstract
Androgen ablation during the initial stages of prostate cancer causes regression of the tumor due to an increase in apoptosis and reduced cellular proliferation. However, prostate cancer invariably progresses to an androgen-independent state for poorly understood reasons. Previous studies showed that c-Jun NH(2) terminal kinase (JNK) is required for 12-O-tetradecanoylphorbol-13-acetate (TPA)- and thapsigargin (TG)-induced apoptosis in the androgen-responsive prostate cancer cell line LNCaP. Androgens protect LNCaP cells from TPA-induced or TG-induced apoptosis via down-regulation of JNK activation. However, the molecular mechanisms of this inhibition are not clear. Here, we systematically investigated the possible regulation of mitogen-activated protein kinase phosphatases/dual-specificity phosphatases during apoptosis of LNCaP cells and found that Vaccinia H1-related protein (VHR/DUSP3) is up-regulated by androgens during inhibition of apoptosis in LNCaP cells, but not in androgen-independent DU145 cells. Ectopic expression of wild-type VHR, but not a catalytically inactive mutant, interfered with TPA- and TG-induced apoptosis. Consistently, small interfering RNA-mediated knockdown of endogenous VHR increased apoptosis in response to TPA or TG in the presence of androgens. Furthermore, COS7 cells stably expressing wild-type VHR, but not a mutant, had a decrease in JNK phosphorylation. In vivo, VHR expression decreased in the androgen-dependent human prostate cancer xenograft CWR22 upon androgen withdrawal and was inversely correlated to JNK phosphorylation. Expression analysis in human prostate cancer specimens showed that VHR is increased in prostate cancer compared with normal prostate. These data show that VHR has a direct role in the inhibition of JNK-dependent apoptosis in LNCaP cells and may therefore have a role in prostate cancer progression.
Highlights
Androgens play an important role in regulating growth, differentiation, and cell death responses in the normal and cancerous prostate
We have shown that androgens protect LNCaP cells from TPA- and TG-induced apoptosis, which is mediated by down-regulation of Jun NH2 terminal kinase (JNK) activity [18]
To determine if MKPs are involved in androgenmediated inhibition of JNK-dependent apoptosis in LNCaP cells, we used quantitative PCR (Q-PCR) to assess possible changes in the expression levels of the MKP family members in cells treated with TPA and TG in the presence or absence of the synthetic androgen R1881
Summary
Androgens play an important role in regulating growth, differentiation, and cell death responses in the normal and cancerous prostate. The actions of androgens are mediated through the androgen receptor (AR), a ligand-activated transcription factor that belongs to the nuclear receptor superfamily [1,2,3]. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). A decrease in circulating androgen levels, by either surgical means (castration) or through androgen deprivation therapy, results in decreased cell proliferation, increased apoptosis, and atrophy in prostate epithelial cells [4]. Prostate tumors relapse and the disease progresses to an androgen-independent state [5]. The molecular mechanisms of transition from androgen dependence to androgen independence remain poorly understood, and little is known about the link between androgens and apoptosis signaling pathways in prostate cancer
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