Inflammation and tumor hypoxia are intimately linked and breast cancer provides a typical example of an inflammation-linked malignant disease. Indeed, breast cancer progression is actively supported by inflammatory components, including IL-1β, and by the hypoxia-inducible factor- (HIF-) 1α. In spite of many attempts where the role of either IL-1βor HIF-1αwas evaluated, detailed mechanisms for their effects on breast cancer cell migration under hypoxia are still unclear. We here report that IL-1βincreased MDAMB231 cell migration under hypoxic conditions along with HIF-1αaccumulation and upregulation of CXCR1, which is transcriptionally regulated by HIF-1α, as well as an increased expression of CXCL8 and NFκB. In addition, IL-1β-induced cell migration in hypoxia was not affected when HIF-1αwas inhibited by either siRNA or Topotecan, well known for its inhibitory effect on HIF-1α. Of interest, HIF-1αinhibition did not reduce NFκB and CXCL8 expression and the reduction of IL-1β-induced cell migration under hypoxia was achieved only by pharmacological inhibition of NFκB. Our findings indicate that inhibition of HIF-1αdoes not prevent the migratory program activated by IL-1βin hypoxic MDAMB231 cells. They also suggest a potential compensatory role of NFκB/CXCL8 pathway in IL-1β-induced MDAMB231 cell migration in a hypoxic microenvironment.
The emerging role of xanthine oxidase inhibition for suppression of breast cancer cell migration and metastasis associated with hypercholesterolemia
