Alterative Expression and Localization of Profilin 1/VASPpS157 and Cofilin 1/VASPpS239 Regulates Metastatic Growth and Is Modified by DHA Supplementation

Abstract

Profilin 1, cofilin 1, and vasodialator stimulated phosphoprotein (VASP) are actin binding proteins (ABP) which regulate actin remodelling and facilitate cancer cell metastases. MiR~17–92 is highly expressed in metastatic tumors and profilin1 and cofilin1 are predicted targets. Docosahexaenoic acid (DHA) inhibits cancer cell proliferation and adhesion. These studies tested the hypothesis that the metastatic phenotype is driven by changes in ABPs including alternative phosphorylation and/or changes in subcellular localization. Additionally, we tested the efficacy of DHA supplementation to attenuate or inhibit these changes. Human lung cancer tissue sections were analyzed for F-actin content and expression and cellular localization of profilin1, cofilin1 and VASP (S157 or S239 phosphorylation). The metastatic phenotype was investigated in A549 and MLE12 cells lines using 8 Br-cAMP as a metastasis inducer and DHA as a therapeutic agent. Migration was assessed by wound assay and expression measured by western blot and confocal analysis. MiR~17–92 expression was measured by qRT-PCR. Results indicated increased expression and altered cellular distribution of profilin1/VASPpS157 but no changes in cofilin1/VASPpS239 in the human malignant tissues compared to normal tissues. In A549 and MLE12 cells, the expression patterns of profilin1/VASPpS157 or cofilin1/VASPpS239 suggested an interaction in regulation of actin dynamics. Furthermore, DHA inhibited cancer cell migration and viability, ABP expression and cellular localization, and modulated expression of miR~17–92 in A549 cells with minimal effects in MLE12 cells. Further investigations are warranted to understand ABP interactions, changes in cellular localization, regulation by miR~17–92, and DHA as a novel therapeutic.

Changes in Vasodilator-Stimulated Phosphoprotein Phosphorylation, Profilin-1, and Cofilin-1 in Accreta and Protection by DHA

“…60 Significantly increased pVASP-S239 levels in cancer cells and tissue counter high actin polymerization, hyperproliferation, invasion, and migration. 13,15,40,61 As shown by our data, increased levels of VASP, pVASP-S239, and cofilin-1 in the context of increased F-actin content suggest a regulatory role of these proteins to counteract trophoblast hypermigration and proliferation. Docosahexaenoic acid reduces cancer cell aggressiveness, which is associated with changes in actin dynamics and apoptotic profiles.…”

“…[34][35][36][37][38][39] Moreover, cofilin-1 levels vary among cancer cell and tumor types and degree of proliferation and migration. 26,[40][41][42] Docosahexaenoic acid (DHA), an anti-inflammatory omega-3 fatty acid often taken as a dietary supplement, has been suggested as a pharmacologic agent in placental disorders, which are often associated with inflammation. [43][44][45][46][47] This suggestion has pathophysiologic plausibility because DHA inhibits cancer cell proliferation, migration, invasion, and survival.…”

New cGMP analogues restrain proliferation and migration of melanoma cells

“…Of note is the observation that PA4 caused nuclear localization of phosphorylated VASP and PA5 cytoplasmic localization. It is reasonable to assume that the different effects attributable to pVASP may correlate with different localization of the protein, as previously reported [ 41 , 42 ], but at the moment, we cannot ascertain whether phosphorylation at S239 happens in the cytoplasm or directly inside the nucleus and we cannot define the role of pVASP in the two cellular compartments. Effects on migration in MNT1 cells could not be tested, but PA4 treatment induced an increase of S239 pVASP with nuclear localization and a decrease in S157 pVASP.…”

Biology of MiR-17-92 Cluster and Its Progress in Lung Cancer

“…With the advancement of precise medical theories and advances in technology, the research of miR-17-92 cluster has continued to deepen in tumor cells, particularly, the roles of miR-17-92 cluster have been continuously explored in lung cancer. Furthermore, the new study has observed that Docosahexaenoic acid (DHA), as a novel therapeutic, modulates expression of miR-17-92 and inhibits cell migration and viability in lung cancer 76 . Intriguingly, accumulating studies show that the roles of miR-17-92 cluster are not clear in lung cancer and need to explore continually in the future.…”