Abstract B36: NF-kappaB-dependent and -independent roles for NIK in regulating GBM cell invasion Conference Paper uri icon

abstract

  • Abstract The aggressive invasion of GBM cells into healthy brain tissue is a major factor contributing to the therapy resistance and poor prognosis of this malignancy. Our recent results demonstrated that the alternative, or noncanonical, NF-kappaB signaling pathway, predominates in the aggressive mesenchymal subtype of GBM. Additionally, NF-kappaB-inducing kinase (NIK), a key upstream activator of noncanonical NF-kappaB signaling, robustly promotes GBM cell invasion and pathogenesis. We demonstrate that expression of NIK is increased in response to exposure to collagen, a major extracellular matrix (ECM) protein present in GBM tumors, with NIK protein levels continuing to increase during invasion in 3D collagen matrices. Interestingly, NIK expression levels correlates with induction of membrane type-1 matrix metalloproteinase (MT1-MMP), a critical enzyme in many invasive tumors, functioning to degrade the basement membrane and ECM during cell migration and invasion. We provide evidence that NIK promotes MT1-MMP activation through increased phosphorylation at membrane protrusions and elevated enzymatic activity. Notably, the activation of MT1-MMP and the pro-invasive effects of NIK persist in the absence of the downstream NF-kappaB transcription factors RelA/p65 and RelB. Together, these data demonstrate a novel ability of NIK to promote GBM cell migration and invasion that is independent of NF-kappaB transcriptional activation functions. The results underscore the therapeutic potential of targeting noncanonical NF-kappaB signaling in these highly invasive tumors. Citation Format: Camille L. Duran, Linda Herrera de Lechuga, Dong W. Lee, Kayla J. Bayless, Raquel Sitcheran. NF-kappaB-dependent and -independent roles for NIK in regulating GBM cell invasion. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr B36.

name of conference

  • Tumor Microenvironment

published proceedings

  • Cancer Research

author list (cited authors)

  • Duran, C. L., Lechuga, L., Lee, D. W., Bayless, K. J., & Sitcheran, R.

publication date

  • January 1, 2015 11:11 AM