Interleukin-4 enhances prostate-specific antigen expression by activation of the androgen receptor and Akt pathway.
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 androgen-responsive 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.
Lee
Soo Ok
SO
Department of Medicine and Pharmacology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Lou
Wei
W
Hou
Min
M
Onate
Sergio A
SA
Gao
Allen C
AC
D000726:Androgen Antagonists / Q000494:pharmacology; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005485:Flutamide / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D015847:Interleukin-4 / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D015741:Metribolone / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017430:Prostate-Specific Antigen / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000187:drug effects; D011944:Receptors, Androgen / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D045165:Testosterone Congeners / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000726:Androgen Antagonists; D002867:Chromones; D004791:Enzyme Inhibitors; D005485:Flutamide; D015847:Interleukin-4; D015741:Metribolone; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017430:Prostate-Specific Antigen; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D011944:Receptors, Androgen; D045165:Testosterone Congeners; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494918:AKT1 protein, human