NF-kB signalling pathway also involved in the prostate cancer development.
NF-kB is an essential protein molecule to enhance the regulation of the gene
expression associated with innate and adaptive immunity and cell
proliferation. When there is no external
stimulus, NF-kB is a dimer remain inactive as they bound with IkB (inhibitor of
kappa B). Through the series of activation, IkB will be degraded which release
NF-kB as free molecule and return it to be activated
form. The degradation is done through the phosphorylation on the specific serine
residues (Ser 177/181 or Ser 176/180) by IkB kinase complex (IKKa or IKKb).
Now, free NF-kB dimer can integrate into the nucleus and then bind to the
enhancer site in DNA, activate the gene in charge on the inflammatory response,
cell growth, metastasis and apoptosis. NF-kB is always at active state caused
by the elevated level of tumour necrosis factor (TNF) and this escalates the
IkB degradation rate. The expression of NF-kB increases at mRNA and protein
level that induced by IL-6 expression. NF-kB also targets on the transcription
regulatory element of the prostate specific antigen (PSA), a foremost marker
for prostate cancer development and progression. This signalling pathway is
closely related with cancer progression, chemoresistance and PSA recurrence.
Soft tissue and bone metastasis is also an indication which showed frequently
in prostate cancer that promoted by NF-kB activation. TNF-? is a
pro-inflammatory cytokine and acts as inducer of NF-kB with the receptors are
figured out that they are highly expressed in prostate cancer. As a consequence,
TNF-? expression was intensified which then cause escalation in terms of
proliferation, angiogenesis, metastasis and resistance to chemotherapeutic
drugs. Quite a number of studies proved that cross-talk mechanism is present
between NF-kB and AR signalling. For instance, p65 of NF-kB can strengthen the
endogenous AR expression and its respective downstream target gene causes the
growth of prostate cancerous cells.