Elevated NIBP/TRAPPC9 mediates tumorigenesis of cancer cells through NFκB signaling
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Yonggang Zhang1,*, Shu Liu2,*, Hong Wang1, Wensheng Yang1, Fang Li1, Fan Yang1, Daohai Yu3, Frederick V. Ramsey3, George P. Tuszyski1 and Wenhui Hu1
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
Wenhui Hu, email:
Keywords: NFκB, TRAPPC9, trans-Golgi network, cancer cells, tumorigenesis
Received: October 09, 2014 Accepted: January 20, 2015 Published: January 31, 2015
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.
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