Abstract
Prostate cancer is a highly prevalent form of cancer that is usually slow-developing and benign. Due to its high prevalence, it is, however, still the second most common cause of death by cancer in men in the West. The higher prevalence of prostate cancer in the West might be due to elevated inflammation from metabolic syndrome or associated comorbidities. NF-κB activation and many other signals associated with inflammation are known to contribute to prostate cancer malignancy. Inflammatory signals have also been associated with the development of castration resistance and resistance against other androgen depletion strategies, which is a major therapeutic challenge. Here, we review the role of inflammation and its link with androgen signaling in prostate cancer. We further describe the role of NF-κB in prostate cancer cell survival and proliferation, major NF-κB signaling pathways in prostate cancer, and the crosstalk between NF-κB and androgen receptor signaling. Several NF-κB-induced risk factors in prostate cancer and their potential for therapeutic targeting in the clinic are described. A better understanding of the inflammatory mechanisms that control the development of prostate cancer and resistance to androgen-deprivation therapy will eventually lead to novel treatment options for patients.
Highlights
The link between NF-κB and cancer was already apparent at its early discovery, since the oncogenic viral NF-κB family protein v-Rel was identified as a κB DNA binding transcription factor [6]
Acquiring a better understanding of the mechanisms that control the development of prostate cancer and resistance to androgen-deprivation therapy remains an unmet clinical need
There is significant positive and negative crosstalk between steroid hormone receptor signaling and inflammatory signaling mediated by NF-κB and other transcription factors
Summary
Inflammation and cancer have been described in the medical literature for millennia [1], and there have been suggestions of a link between inflammation and cancer for centuries [2], but the significant overlap in molecular mechanisms between inflammation and cancer has only begun to be appreciated in recent decades [3,4]. The transactivating (class II) NF-κB family members (RelA, RelB and c-Rel) are kept inactive by binding to the ankyrin repeat domain of inhibitor of NF-κB. In the non-canonical pathway, p52 primarily activates NF-κB transcription, together with together with the transactivating RelB subunit (Figure 1b). NF-κB subunits in red, and IκB proteins in orange In both pathways, phosphorylation leads to to the proteasomal removal of inhibitory domains (e.g., in case of p100) or proteins (in case of IκBα) the proteasomal removal of inhibitory domains (e.g., in case of p100) or proteins (in case of IκBα) that that prevent the NF-κB dimers from entering the nucleus to activate transcription. NF-κB subunits do not exclusively interact with each other, and other “hybrid” active transcription complexes can occur where DNA binding is provided by p50 or p52, but with transactivation by a different kind of protein. Bcl-3 in complex with NF-κB is known to promote pro-survival and pro-proliferation transcription and suppress pro-inflammatory transcription after protein kinase C (PKC) activation by phorbol ester stimulation [19,20], which is important for the development of certain cancers
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