Elevated NIBP/TRAPPC9 mediates tumorigenesis of cancer cells through NFκB signaling

Regulatory mechanisms underlying constitutive and inducible NF kappa B activation in cancer remain largely unknown. Here we investigated whether a novel NIK-and IKK2-binding protein (NIBP) is required for maintaining malignancy of cancer cells in an NF kappa B-dependent manner. Real-time polymerase chain reaction analysis of a human cancer survey tissue-scan cDNA array, immunostaining of a human frozen tumor tissue array and immunoblotting of a high-density reverse-phase cancer protein lysate array showed that NIBP is extensively expressed in most tumor tissues, particularly in breast and colon cancer. Lentivirus-mediated NIBP shRNA knockdown significantly inhibited the growth/proliferation, invasion/migration, colony formation and xenograft tumorigenesis of breast (MDA-MB-231) or colon (HCT116) cancer cells. NIBP overexpression in HCT116 cells promoted cell proliferation, migration and colony formation. Mechanistically, NIBP knockdown in cancer cells inhibited cytokine-induced activation of NF kappa B luciferase reporter, thus sensitizing the cells to TNF alpha-induced apoptosis. Endogenous NIBP bound specifically to the phosphorylated IKK2 in a TNF alpha-dependent manner. NIBP knockdown transiently attenuated TNF alpha-stimulated phosphorylation of IKK2/p65 and degradation of I.Ba. In contrast, NIBP overexpression enhanced TNF alpha-induced NF kappa B activation, thus inhibiting constitutive and TNF alpha-induced apoptosis. Collectively, our data identified important roles of NIBP in promoting tumorigenesis via NF kappa. signaling, spotlighting NIBP as a promising target in cancer therapeutic intervention.