Breast cancer cell invasiveness is stimulated by loss of membrane interaction of actinbinding protein profilin1 via altered phosphoinositide metabolism

Abstract

Profilin1 (Pfn1) belongs to a class of actin‐binding protein cytoskeletal function of which is negatively regulated by its interaction with membrane phosphoinositides (PPI). In stark contrast to most physiological scenarios where loss of Pfn1 significantly impairs normal cell migration and invasion through inhibition of actin polymerization, breast cancer cells exhibit hyper‐migratory phenotype in vitro and enhanced hematogenous dissemination from primary tumor in vivo upon depletion of Pfn1, the underlying mechanism of which is not easily explained by Pfn1's cytoskeletal function. Through knockdown and overexpression studies in multiple cell lines, we show that Pfn1 plays a key role in determining the cellular profile of various PPIs including PI(4,5)P2, PIP3 and PI(3,4)P2 Specifically, Pfn1 promotes PI(4,5)P2 and inhibits membrane accumulation of PI3K‐generated PPIs including PIP3 and PI(3,4)P2, a feature related to Pfn1's PPI interaction. Kinetics of PI3K signaling output suggest that loss of Pfn1 enhances sustenance of PI3K signaling by inhibiting an antagonistic pathway, a finding that correlates to Pfn1‐dependent regulation of PTEN. We establish Pfn1‐dependent alteration of multiple pro‐metastatic cytokines and membrane recruitment of selective PI(3,4)P2‐dependent pro‐migratory protein complexes, the latter in particular linking to hyper‐migratory and hyper‐invasive phenotypes of Pfn1‐deficient breast cancer cells. In summary, these findings establish novel regulation of cell migration by lipid signaling via membrane interaction of actin‐binding protein.Support or Funding InformationNIH 2R01CA 108607This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.