Pancreatic cancer has the worst prognosis among major
malignancies, largely due to its highly invasive property and difficulty in early detection. Mechanistic insights into cancerous transformation and especially metastatic progression are imperative for developing novel treatment strategies. The actin-regulating
protein CAP1 is implicated in human
cancers, while the role still remains elusive. In this study, we investigated roles for
CAP1 and its phosphor-regulation in
pancreatic cancer cells. No evidence supports remarkable up-regulation of
CAP1 in the panel of
cancer cell lines examined. However, knockdown of
CAP1 in
cancer cells led to enhanced stress fibers, reduced cell motility and invasion into
Matrigel. Phosphorylation of
CAP1 at the S308/S310 tandem regulatory site was elevated in
cancer cells, consistent with hyper-activated GSK3 reported in
pancreatic cancer. Inhibition of GSK3, a
kinase for S310, reduced cell motility and invasion. Moreover, phosphor mutants had defects in alleviating actin stress fibers and rescuing the reduced invasiveness in the CAP1-knockdown PANC-1 cells. These results suggest a required role for transient phosphorylation for
CAP1 function in controlling
cancer cell invasiveness. Depletion of
CAP1 also reduced FAK activity and cell adhesion, but did not cause significant alterations in ERK or cell proliferation.
CAP1 likely regulates
cancer cell invasiveness through effects on both actin filament turnover and cell adhesion. Finally, the
growth factor PDGF induced
CAP1 dephosphorylation, suggesting
CAP1 may mediate extracellular signals to control
cancer cell invasiveness. These findings may ultimately help develop strategies targeting
CAP1 or its regulatory signals for controlling the invasive cycle of the disease.