Interleukin-4 enhances prostate-specific antigen expression by activation of the androgen receptor and Akt pathway

Abstract

Androgen receptor (AR) plays an important role in the development and progression of prostate cancer upon the action of androgen through the binding of the androgenresponsive elements (AREs) on the target genes. Abnormal activation of the AR by nonandrogen has been implicated in the progression of androgen-independent prostate cancer. The levels of interleukin-4 (IL-4) are significantly elevated in sera of patients with hormone refractory prostate cancer. The potential role of IL-4 on the activation of AR was investigated in prostate cancer cells. IL-4 enhances AR-mediated prostate-specific antigen (PSA) expression and ARE-containing gene activity through activation of the AR in the androgen ablation condition in human prostate cancer cells. The AR can also be sensitized by IL-4 and activated by significantly lower levels of androgen (10 pm of R1881) in prostate cancer cells. IL-4 enhances nuclear translocation of AR and increases binding of the AR to the ARE in LNCaP prostate cancer cells. Blocking of the Akt pathway by an Akt-specific inhibitor LY294002 abrogates IL-4-induced PSA expression and AR signaling. These results demonstrate that IL-4 enhances PSA expression through activation of the AR and Akt signaling pathways in LNCaP prostate cancer cells. Understanding IL-4-induced signaling leading to abnormal activation of AR will provide insights into the molecular mechanisms of androgen-independent progression of prostate cancer cells.

Serum/glucocorticoid-induced protein kinase-1 facilitates androgen receptor-dependent cell survival

“…The ARE-LUC reporter was described previously. 41 The reporter gene assay was performed as described previously. 12,33,38,40 Briefly, cells plated in six-well tissue culture plates were transfected with reporter constructs using the Cytofectenet reagent (BioRad) according to the manufacturer's protocol.…”

Interleukin‐4 stimulates androgen‐independent growth in LNCaP human prostate cancer cells

“…We have demonstrated previously that IL-4 activates AR signaling in a low level of androgen or in the absence of androgen [19]. To examine the effects of IL-4 expression on prostate cancer cell growth, we developed IL-4 overexpressing cells by introduction of a fulllength IL-4 cDNA into IL-4-negative LNCaP cells.…”

“…Previous studies demonstrated that IL-4 enhances AR activation in prostate cancer cells [19]. To test whether overexpression of IL-4 enhances the expression of an endogenous, androgen-regulated PSA, the expression of PSA was compared among IL-4 express- (normal FBS condition).…”

“…Previous studies demonstrated that IL-4 activates AR-mediated gene expression by activation of the AR in a ligandindependent manner or in the presence of very low levels of androgen [19]. Further studies showed that IL-4-mediated AR activation involved in activation of NF-kB [20].…”

Phosphoinositide 3-OH kinase p85α and p110β are essential for androgen receptor transactivation and tumor progression in prostate cancers

“…Luciferase and SEAP reporter assay A luciferase reporter construct controlled by synthetic androgen response elements (ARE-LUC) and the control reporter construct CMV-SEAP, expressing secreted alkaline phosphatase (SEAP) under the control of the cytomegalovirus (CMV) promoter, were described previously (Lee et al, 2003;Shanmugam et al, 2007). For PI3K overexpression experiments, cells were plated in six-well tissue culture plates and co-transfected on the following day with 1.0 mg ARE-LUC, 0.5 mg CMV-SEAP and various amount of PI3K constructs as indicated in the figure using the LipoFectamine reagent (Invitrogen).…”