The role of IKK-alpha in colorectal cancer


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Meera Patel1,Hannah Hood2,Jean Quinn3,Antonia Roseweir3,Arfon Powell4,Paul Horgan3,Donald McMcMillan3,Joanne Edwards1
1Institute of Cancer Sciences, University of Glasgow,2School of Medicine, University of Glasgow,3Academic Unit of Surgery, University of Glasgow,4School of Medicine, Cardiff University

Abstract

Background

Pharmacological inhibition of key non-canonical NF-κB kinase, IKKα, has emerged as a therapeutic target in a number of solid malignancies including prostate, breast and pancreatic cancer. Therefore, it is of interest to understand the role of this pathway in colorectal cancer.

Method

Using immunohistochemistry, IKKα expression was investigated in a tissue microarray of 1030 patients who had undergone surgery for stage I-III colorectal cancer. Immunofluorescence was used to investigate the cellular distribution and localisation of IKKα.

Results

High expression of IKKα was associated with adverse pathological tumour features; increasing T stage (p=0.012), poor tumour differentiation (p=0.010), tumour necrosis (p=0.013) and low proliferation (p=0.013). High expression of IKKα was associated with BRAF wild-type status (p=0.011). An unfamiliar perinuclear ‘punctate’ pattern of IKKα expression was also observed, and this was associated with significantly reduced cancer-specific survival (p<0.001). This was potentiated in patients with BRAF wild-type status (p=0.005). To investigate this pattern further, IKKα phosphorylation sites S176 and T23 were investigated with immunohistochemistry; however, punctate IKKα expression was not observed. Using immunofluorescence, markers of cellular transport machinery (RAB5, RAB7 and Golgi 58) were investigated to further understand the distribution and localisation of IKKα. This demonstrated IKKα co-localised with a marker of the Golgi apparatus (Golgi 58).

Conclusion

High expression of IKKα was associated with an adverse tumour phenotype and poor survival in patients undergoing surgery for stage I-III colorectal cancer. Punctate expression of IKKα was observed and was associated with the Golgi apparatus or indeed a Golgi-related structure. This raises a number of possible hypotheses that require further investigation. Altogether, inhibition of IKKα in colorectal cancer offers a potentially new therapeutic strategy. In vitro studies using IKKα inhibitors have begun.