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

// Yonggang Zhang 1,* , Shu Liu 2,* , Hong Wang 1 , Wensheng Yang 1 , Fang Li 1 , Fan Yang 1 , Daohai Yu 3 , Frederick V. Ramsey 3 , George P. Tuszyski 1 and Wenhui Hu 1 1 Department of Neuroscience, Temple University School of Medicine, Philadelphia, PA, USA 2 Department of Biotherapy, The Forth Affiliated Hospital, China Medical University, Shenyang, Liaoning, China 3 Department of Clinical Sciences, Temple University School of Medicine, Philadelphia, PA, USA * These authors contributed equally to this work Correspondence: Wenhui Hu, email: // Keywords : NFκB, TRAPPC9, trans-Golgi network, cancer cells, tumorigenesis Received : October 09, 2014 Accepted : January 20, 2015 Published : January 31, 2015 Abstract Regulatory mechanisms underlying constitutive and inducible NFκB 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 NFκB-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 NFκB luciferase reporter, thus sensitizing the cells to TNFα-induced apoptosis. Endogenous NIBP bound specifically to the phosphorylated IKK2 in a TNFα-dependent manner. NIBP knockdown transiently attenuated TNFα-stimulated phosphorylation of IKK2/p65 and degradation of IκBα. In contrast, NIBP overexpression enhanced TNFα-induced NFκB activation, thus inhibiting constitutive and TNFα-induced apoptosis. Collectively, our data identified important roles of NIBP in promoting tumorigenesis via NFκΒ signaling, spotlighting NIBP as a promising target in cancer therapeutic intervention.