NF-κB, chemokine gene transcription and tumour growth

Abstract

Chemokines are small, pro-inflammatory cytokines. There are four subfamilies of chemokines on the basis of their structural similarity — CXC-, CX₃C-, C- and CC-chemokines. In the CXC family of chemokines, some are angiogenic (with a conserved Glu-Leu-Arg (ELR) motif at the amino terminus) and some are angiostatic (which do not have an ELR motif at the amino terminus). Normally, the transcription of chemokine genes is tightly regulated. However, many chemokine genes are constitutively transcribed by tumour cells at relatively high levels. Transcription of the angiogenic CXC-chemokine genes is modulated by nuclear factor-κB (NF-κB). When the inhibitor of NF-κB (IκB) is phosphorylated by IκB kinase (IKK), IκB is targeted for ubiquitylation and degradation by the proteasome, which frees NF-κB to translocate to the nucleus and activate gene transcription. The constitutive activation of IKK in tumour cells leads to the endogenous transcription of certain angiogenic and tumorigenic chemokine genes, including CXCL1 and CXCL8. Melanoma tumour cells have endogenous activation of two other kinases that modulate NF-κB activity: NF-κB-inducing kinase (NIK) and AKT, a serine/threonine kinase that affects the phosphorylation and activation of RELA/p65. NF-κB modulates gene expression in the context of a promoter/enhancer that comprises other positive and negative regulatory factors. Gene transcription of chemokines is the result of the combined interaction of NF-κB with factors that modulate histone acetylation or deacetylation and factors that interact with other proteins to stabilize or destabilize the transcriptional machinery. Chemokine gene transcription is regulated by an enhanceosome-like structure. For CXCL1, this comprises SP1, NF-κB, the high-mobility group protein HMGIY and immediate upstream region (IUR) elements. For CXCL8, it comprises AP1, nuclear factor induced by IL-6 (NF-IL-6), NF-κB and a negative regulatory factor (NRF). The inhibition of activation of NF-κB offers potential for the therapeutic intervention of tumour growth.