Additionally,NF-kB signalling pathway also involved in the prostate cancer development.
NF-kB is an essential protein molecule to enhance the regulation of the geneexpression associated with innate and adaptive immunity and cellproliferation. When there is no externalstimulus, NF-kB is a dimer remain inactive as they bound with IkB (inhibitor ofkappa B). Through the series of activation, IkB will be degraded which releaseNF-kB as free molecule and return it to be activatedform.
The degradation is done through the phosphorylation on the specific serineresidues (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 theenhancer site in DNA, activate the gene in charge on the inflammatory response,cell growth, metastasis and apoptosis. NF-kB is always at active state causedby the elevated level of tumour necrosis factor (TNF) and this escalates theIkB degradation rate. The expression of NF-kB increases at mRNA and proteinlevel that induced by IL-6 expression.
NF-kB also targets on the transcriptionregulatory element of the prostate specific antigen (PSA), a foremost markerfor prostate cancer development and progression. This signalling pathway isclosely related with cancer progression, chemoresistance and PSA recurrence.Soft tissue and bone metastasis is also an indication which showed frequentlyin prostate cancer that promoted by NF-kB activation. TNF-? is apro-inflammatory cytokine and acts as inducer of NF-kB with the receptors arefigured out that they are highly expressed in prostate cancer. As a consequence,TNF-? expression was intensified which then cause escalation in terms ofproliferation, angiogenesis, metastasis and resistance to chemotherapeuticdrugs. Quite a number of studies proved that cross-talk mechanism is presentbetween NF-kB and AR signalling.
For instance, p65 of NF-kB can strengthen theendogenous AR expression and its respective downstream target gene causes thegrowth of prostate cancerous cells.