Mitochondrial IκBα facilitates metastasis formation in lung cancer through endothelial activation

Lung cancer is the most common cause of cancer death worldwide, and no treatment to date is effective, so are needed novel approaches to either prevent or treat cancer. The vascular microenvironment plays an important role in whole process as it is actively involved in all aspects of tumor progression and metastasis, contributing to the traffic of oxygen, nutrients and waste, also intervening in the regulation of the immune component. The main route of cancer cells dissemination is therefore represented by endothelial cells (ECs) which have gained the spotlight in the distinctive characteristics of cancer. Here, we found that overexpression in lung cancer cells of IκBα, a key player in NF-κB pathway, induces robust endothelial activation through the metabolic switch, as well as increased proliferation and the number of colonies and decreased apoptosis of A549 cells. In particular, this effect seems to be maximized by the localization of IκBα in the mitochondrion (MTS-IκBα). MTS-IκBα increases the expression of endothelial and inflammatory adhesion molecules, such as intercellular adhesion molecule-1 (ICAM1) and vascular cell adhesion molecule-1 (VCAM1), thereby promoting tumor cell adhesion to ECs and transmigration through them. MTS-IκBα plays a role in metabolism increasing the glycolytic rate of A549 tumor cells. In line with this, pretreatment of tumor cells with 2-Deoxy-D-glucose (2DG), a glucose analog that targets glucose metabolism to deprive tumor cells of energy, abrogated the pro-adhesive effect of its secretome on endothelial cells. 2DG can effectively slow cell growth in specific tumor cells and can be combined with other therapeutic agents or radiotherapy to show a synergistic antitumor effect.