Constitutive activation of IkappaB kinase alpha and NF-kappaB in prostate cancer cells is inhibited by ibuprofen.
Apoptotic pathways controlled by the Rel/NF-kappaB family of transcription factors may regulate the response of cells to DNA damage. Here, we have examined the NF-kappaB status of several prostate tumor cell lines. In the androgen-independent prostate tumor cells PC-3 and DU-145, the DNA-binding activity of NF-kappaB was constitutively activated and IkappaB-alpha levels were decreased. In contrast, the androgen-sensitive prostate tumor cell line LNCaP had low levels of NF-kappaB which were upregulated following exposure to cytokines or DNA damage. The activity of the IkappaB-alpha kinase, IKKalpha, which mediates NF-kappaB activation, was also measured. In PC-3 cells, IKKalpha activity was constitutively active, whereas LNCaP cells had minimal IKKalpha activity that was activated by cytokines. The anti-inflammatory agent ibuprofen inhibited the constitutive activation of NF-kappaB and IKKalpha in PC-3 and DU-145 cells, and blocked stimulated activation of NF-kappaB in LNCaP cells. However, ibuprofen did not directly inhibit IkappaB-alpha kinase. The results demonstrate that NF-kappaB is constitutively activated in the hormone-insensitive prostate tumor cell lines PC-3 and DU-145, but not in the hormone responsive LNCaP cell line. The constitutive activation of NF-kappaB in prostate tumor cells may increase expression of anti-apoptotic proteins, thereby decreasing the effectiveness of anti-tumor therapy and contributing to the development of the malignant phenotype.
Palayoor
S T
ST
Radiation Oncology Branch, National Cancer Institute, 9000 Rockville Pike, Bethesda, Maryland, MD 20892, USA.
Youmell
M Y
MY
Calderwood
S K
SK
Coleman
C N
CN
Price
B D
BD
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D004789:Enzyme Activation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051550:I-kappa B Kinase; D007052:Ibuprofen / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D007052:Ibuprofen