title: WAVE3-NFκB interplay is essential for the survival and invasion of cancer cells.
abstract: The WAVE3 cytoskeletal protein promotes cancer invasion and metastasis. We have shown that the WAVE3-mediated activation of cancer cell invasion is due, in part, to its regulation of expression and activity of key metalloproteinases (MMPs), including MMP9, which is centrally involved in invadopodia-mediated degradation of the extracellular matrix (ECM). MMP9 is also a major NFκB target gene, suggesting a potential linkage of WAVE3 to this pathway, which we sought to investigate. Mechanistically, we found that loss of WAVE3 in cancer cells leads to inhibition of NFκB signaling as a result of a decrease in the nuclear translocation of NFκB and therefore loss of activation of NFκB target genes. Conversely, overexpression of WAVE3 was sufficient to enhance NFκB activity. Both pharmacologic and genetic manipulations of NFκB effector molecules show that the biological consequence of loss of WAVE3 function in the NFκB pathway result the inhibition of invadopodia formation and ECM degradation by cancer cells, and these changes are a consequence of decreased MMP9 expression and activity. Loss of WAVE3 also sensitized cancer cells to apoptosis and cell death driven by TNFα, through the inhibition of the AKT pro-survival pathway. Our results identify a novel function of WAVE3 in NFκB signaling, where its activity is essential for the regulation of invadopodia and ECM degradation. Therefore, targeted therapeutic inhibition of WAVE3 will sensitize cancer cells to apoptosis and cell death, and suppress cancer invasion and metastasis.
authors.affiliation: Department of Molecular Cardiology, Cleveland Clinic Lerner Institute, Cleveland, Ohio, United States of America.
authors.forename: Gangarao
authors.initials: G
authors.lastname: Davuluri
authors.affiliation: Department of Molecular Cardiology, Cleveland Clinic Lerner Institute, Cleveland, Ohio, United States of America.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Augoff
authors.affiliation: Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: William P
authors.initials: WP
authors.lastname: Schiemann
authors.affiliation: Department of Molecular Cardiology, Cleveland Clinic Lerner Institute, Cleveland, Ohio, United States of America.
authors.forename: Edward F
authors.initials: EF
authors.lastname: Plow
authors.affiliation: Department of Molecular Cardiology, Cleveland Clinic Lerner Institute, Cleveland, Ohio, United States of America.
authors.forename: Khalid
authors.initials: K
authors.lastname: Sossey-Alaoui
mesh_terms: D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000235:genetics; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D000069261:Podosomes / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D051300:Wiskott-Aldrich Syndrome Protein Family / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D016328:NF-kappa B; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; C120153:WASF3 protein, human; D051300:Wiskott-Aldrich Syndrome Protein Family; D020780:Matrix Metalloproteinase 9