Constitutive activation of IκB kinase α and NF-κB in prostate cancer cells is inhibited by ibuprofen

Abstract

Apoptotic pathways controlled by the Rel/NF-kB family of transcription factors may regulate the response of cells to DNA damage. Here, we have examined the NFkB 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-kB was constitutively activated and IkB-a levels were decreased. In contrast, the androgen-sensitive prostate tumor cell line LNCaP had low levels of NF-kB which were upregulated following exposure to cytokines or DNA damage. The activity of the IkB-a kinase, IKKa, which mediates NF-kB activation, was also measured. In PC-3 cells, IKKa activity was constitutively active, whereas LNCaP cells had minimal IKKa activity that was activated by cytokines. The anti-in¯ammatory agent ibuprofen inhibited the constitutive activation of NF-kB and IKKa in PC-3 and DU-145 cells, and blocked stimulated activation of NF-kB in LNCaP cells. However, ibuprofen did not directly inhibit IkB-a kinase. The results demonstrate that NF-kB 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-kB in prostate tumor cells may increase expression of anti-apoptotic proteins, thereby decreasing the e ectiveness of anti-tumor therapy and contributing to the development of the malignant phenotype.

Quinazoline-based α1-adrenoceptor antagonists induce prostate cancer cell apoptosis via TGF-β signalling and IκBα induction

“…These reports together with the observed upregulation of IkBa in prostate cancer cells may provide a mechanism to explain the increased apoptosis and reduced tumour vascularity in prostate cancer specimens (Keledjian et al, 2001). Constitutive activation of NF-kB has been reported in many tumours (Baldwin, 1996), including androgen-independent prostate cancer cells (Pajonk et al, 1999;Palayoor et al, 1999;Suh et al, 2002) and oestrogen receptor-negative breast cancer cells (Biswas et al, 2001). This activation of NF-kB survival signalling is believed to provide a growth advantage in androgen-independent prostate cancer cells by suppressing apoptosis and inducing cell adhesion and angiogenic potential (Huang et al, 2001;Gasparian et al, 2002).…”

Activation of nuclear factor-κB in human prostate carcinogenesis and association to biochemical relapse

“…In addition to its role in prostate cancer behaviour (Andela et al, 2003), NF-kB activation is also implicated in chemo-and radioresistance. These observations are complemented by studies showing that NF-kB inhibition is a promising strategy for prostate cancer treatment, and, particularly, as a chemo-or radio-sensitisation strategy (Palayoor et al, 1999;Altuwaijri et al, 2003;Flynn et al, 2003;Kikuchi et al, 2003;Chendil et al, 2004). Clearly, inhibition of NF-kB may potentiate the antineoplastic effect of conventional chemotherapeutic agents (Sanchez-Perez et al, 2002).…”

Induction of proteasome expression in skeletal muscle is attenuated by inhibitors of NF-κB activation

“…Thus EPA, which prevents nuclear migration of NF-kB in murine myotubes in response to PIF by stabilising the cytosolic I-kB/NF-kB complex (Whitehouse and Tisdale, 2003), possibly by interfering with I-kB phosphorylation (Novak et al, 2003), has been shown to attenuate the development of further weight loss in weight-losing patients with pancreatic cancer (Wigmore et al, 2000) and produce an increase in lean body mass when combined with a high protein energy dense nutritional supplement (Barber et al, 1999). The anti-inflammatory agent, ibuprofen, has been shown to inhibit constitutive activation of NFkB and IKKa in prostate cancer cells (Palayoor et al, 1999), and when combined with megestrol acetate produced an increase in body weight in gastrointestinal cancer patients (McMillan et al, 1999), while megestrol acetate alone produced a decrease in body weight. Another anti-inflammatory agent, thalidomide, can also block NF-kB activation through inhibition of IKK (Keifer et al, 2001), and has been shown to promote weight gain in HIV-infected patients receiving treatment for tuberculosis (Reys-Teran et al, 1996), and is currently under evaluation for the treatment of cancer cachexia.…”