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WAVE3-NFκB interplay is essential for the survival and invasion of cancer cells.

Davuluri G, Augoff K, Schiemann WP, Plow EF, Sossey-Alaoui K - PLoS ONE (2014)

Bottom Line: 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.Our results identify a novel function of WAVE3 in NFκB signaling, where its activity is essential for the regulation of invadopodia and ECM degradation.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Cardiology, Cleveland Clinic Lerner Institute, Cleveland, Ohio, United States of America.

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.

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Related in: MedlinePlus

Model describing how the WAVE3-NFκB interplay modulates the molecular signaling pathways that regulate cancer invasion and metastasis.The interrelationship between WAVE3 and NFκB/Akt signaling regulates pro-survival genes to acquire chemoresistance and activates ECM degradation though the regulation of invadopodia formation and MMP9 expression and activity. The regulation of both pro-survival genes and the ECM degradation are required for the regulation of cancer cell invasion and metastasis.
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pone-0110627-g009: Model describing how the WAVE3-NFκB interplay modulates the molecular signaling pathways that regulate cancer invasion and metastasis.The interrelationship between WAVE3 and NFκB/Akt signaling regulates pro-survival genes to acquire chemoresistance and activates ECM degradation though the regulation of invadopodia formation and MMP9 expression and activity. The regulation of both pro-survival genes and the ECM degradation are required for the regulation of cancer cell invasion and metastasis.

Mentions: In conclusion, we have identified a novel role of WAVE3 in NFκB signaling and in the invasion-metastasis cascade through its regulation of invadopodia formation and MMP9 activation. It is also interesting to note that loss of WAVE3 can sensitize cancer cells to TNFα-induced apoptosis and cell death (Fig. 9). We therefore believe that these regulatory functions of WAVE3 could be targeted to inhibit cancer cell invasion and metastasis.


WAVE3-NFκB interplay is essential for the survival and invasion of cancer cells.

Davuluri G, Augoff K, Schiemann WP, Plow EF, Sossey-Alaoui K - PLoS ONE (2014)

Model describing how the WAVE3-NFκB interplay modulates the molecular signaling pathways that regulate cancer invasion and metastasis.The interrelationship between WAVE3 and NFκB/Akt signaling regulates pro-survival genes to acquire chemoresistance and activates ECM degradation though the regulation of invadopodia formation and MMP9 expression and activity. The regulation of both pro-survival genes and the ECM degradation are required for the regulation of cancer cell invasion and metastasis.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4199728&req=5

pone-0110627-g009: Model describing how the WAVE3-NFκB interplay modulates the molecular signaling pathways that regulate cancer invasion and metastasis.The interrelationship between WAVE3 and NFκB/Akt signaling regulates pro-survival genes to acquire chemoresistance and activates ECM degradation though the regulation of invadopodia formation and MMP9 expression and activity. The regulation of both pro-survival genes and the ECM degradation are required for the regulation of cancer cell invasion and metastasis.
Mentions: In conclusion, we have identified a novel role of WAVE3 in NFκB signaling and in the invasion-metastasis cascade through its regulation of invadopodia formation and MMP9 activation. It is also interesting to note that loss of WAVE3 can sensitize cancer cells to TNFα-induced apoptosis and cell death (Fig. 9). We therefore believe that these regulatory functions of WAVE3 could be targeted to inhibit cancer cell invasion and metastasis.

Bottom Line: 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.Our results identify a novel function of WAVE3 in NFκB signaling, where its activity is essential for the regulation of invadopodia and ECM degradation.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Cardiology, Cleveland Clinic Lerner Institute, Cleveland, Ohio, United States of America.

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.

Show MeSH
Related in: MedlinePlus