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  • ABT-888 (Veliparib) br Fig Inhibition of cadherin


    Fig. 8. Inhibition of cadherin-11 reverses the increased motility of ADD1-deficient lung cancer cells. (A, B) Representative im-munoblots showing expression of different cadherins and densitometric quantification of the cadherin-11 protein level in the control, ADD1, or ADD3-depleted H1573 cells. (C, D) Cadherin-11 was transiently depleted by siRNA in control and ADD1-deficient H1573 cells. (C) Immunoblotting analysis shows the efficiency of cadherin-11 depletion. (D) Results of the transfilter migration assay of the control and ADD1-deficient H1573 cells with and without cadherin-11 depletion. (E, F) Transfilter migration data for the control and ADD1-deficient H1573 cells treated with either anti-cadherin-11 antibody or control IgG. Data are presented as mean ± SE (n = 3); *p < 0.05; **p < 0.005.
    mesenchymal cells and is upregulated in different solid tumors [66–68]. Importantly, several studies demonstrated that cadherin-11 drives cancer cell motility [66–68], which is consistent with the cadherin-11 activity observed in adducin-depleted NSCLC cells (Fig. 8). How does cadherin-11 accelerate motility of cancer cells remain poorly under-stood, although overexpression of this protein in mesenchymal stem cells and fibroblasts was shown to dramatically affect the contractile properties of the cells and production of ECM proteins [69,70].
    The observed regulation of cadherin-11 expression in NSCLC cells represents an unusual activity of adducins. Only one previous study documented decreased expression of adhesion-related proteins, sy-naptopodin, and alpha-actinin, in podocytes of ADD2-null mice [71]. The mechanisms of adducin-dependent regulation of protein expression await further investigations, however, at least two possibilities could be envisioned. One possibility is that adducins affect cadherin-11 expres-sion indirectly, by modulating cytoskeleton-dependent activity of serum response factor (SRF). An alternative possibility would be a di-rect effect of ADD1 on cadherin-11 transcription in the nucleus. The 
    former mechanism is based on a recent report that cadherin-11 ex-pression is controlled by SRF during mesenchymal stem cell differ-entiation [69]. On the other hand, SRF is a transcriptional factor, which activity is regulated by the ABT-888 (Veliparib) cytoskeleton and specifically by the availability of monomeric actin [72,73]. Since altered adducin expres-sion could shift the ratio of monomeric–to-polymeric actin in epithelial cells [31], this may result in altered SRF activity and SRF-dependent expression of cadherin-11. The possibility of direct adducin-dependent regulation of cadherin-11 expression is based on the fact that adducins possess nuclear localization signals and could translocate into the nu-cleus (Fig. 1; Suppl. Fig. 7) [30,74]. Interestingly, nuclear retention of ADD1 was shown to be significantly higher as compared to the ADD3 isoform [74], which is consistent with its superior ability to repress cadherin-11 expression (Fig. 8). In the nucleus, ADD1 was shown to interact with RNA polymerase and a transcription factor, ZNF331, however, the functional consequences of such interactions have not been explored [74].
    S. Lechuga et al.
    In conclusion, the results of our study demonstrate that adducins, especially ADD1, act as potent inhibitors of migration and invasion of NSCLC cells and non-transformed bronchial epithelial cells. Furthermore, we identified two distinct mechanisms of adducin-de-pendent regulation of cell motility depending on the level of ADD1 expression and involving modulation of ECM adhesion and regulation of cadherin-11expression. Since adducins are either downregulated or functionally inhibited by pro-oncogenic signaling pathways, dysfunc-tion of these membrane skeleton proteins is likely to contribute to the metastatic dissemination of lung cancer cells. Additional studies are warranted to dissect possible roles and mechanisms of adducins in tumor progression and metastasis.
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    Transparency document
    The Transparency document associated with this article can be found, in online version.
    We thank Drs. Samir M. Hanash, John Minna and Hong-Chen Chen for providing valuable reagents for this study. Microscopy was per-formed at the VCU Department of Anatomy and Neurobiology Microscopy Facility, supported, in part, with funding from the National Institute of Health (NIH)-NINDS, Imaging Center Core grant 5P30NS047463 and NIH-NCI, Massey Cancer Center Support grant P30CA016059. Some imaging experiments were performed using a Leica SP8 confocal microscope that was purchased with funding from the National Institutes of Health SIG grant S10-OD019972. This work was supported by the NIH-NIDDK grant R01 DK108278 to A.I.I.
    [15] V. Bennett, J. Healy, Membrane domains based on ankyrin and spectrin associated with cell-cell interactions, Cold Spring Harb. Perspect. Biol. 1 (2009) a003012.