A splicing variant of NME1 negatively regulates NF-{kappa}B signaling and inhibits cancer metastasis by interacting with IKK{beta} [Cell Biology]

May 8th, 2014 by You, D.-J., Park, C. R., Lee, H. B., Moon, M. J., Kang, J.-H., Lee, C., Oh, S.-H., Ahn, C., Seong, J. Y., Hwang, J.-I.

IKKβ functions as a principal upstream activator of the canonical NF-κB pathway by phosphorylating IκB, leading to its proteasomal degradation. Since IKKβ is considered a therapeutic target, understanding its regulation may facilitate the design of efficient regulators of this molecule. Here, we report a novel IKKβ-interacting molecule: NME1L, a splicing variant of the NME1 protein. NME1 has attracted attention in cancer research because of its anti-metastatic activity and reduced expression in multiple aggressive types of cancer. However, the effect was just moderate but not dramatic in anti-cancer activities. We found that only NME1L interacts with IKKβ. Exogenous expression of NME1L resulted in a potent decrease in TNFα-stimulated NF-κB activation, while knockdown of NME1/NME1L with shRNA enhanced activity of NF-κB. NME1L down-regulates IKKβ signaling by blocking IKKβ-mediated IκB degradation. When NME1L was introduced into highly metastatic HT1080 cells, the mobility was efficiently inhibited. Furthermore, in metastasis assay, NME1L-expressing cells did not colonize the lung. Based on these results, NME1L is a potent anti-metastatic protein and may be a useful weapon to fight against cancers.
  • Posted in Journal of Biological Chemistry, Publications
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