Pancreatic ductal
adenocarcinoma (PDA) is one of the most lethal
malignancies worldwide.
All-trans retinoic acid (ATRA) has been used as an antistromal agent in PDA, and its antitumor effect has also been reported in various kinds of
cancer, including PDA. Inhibition of
p21-activated kinases (PAKs) is associated with decreased
tumor growth and increased
gemcitabine sensitivity. The aim of this study was to evaluate the inhibitory effects of ATRA alone and in combination with
gemcitabine on cell growth and migration of wild-type and
gemcitabine-resistant PDA cells and the potential mechanism(s) involved. Human (MiaPaCa-2) and murine (TB33117) PDA cell lines were incubated in increasing concentrations of
gemcitabine to establish resistant clones. Cell growth, clonogenicity, and migration/invasion were determined using a
sulforhodamine B assay, a colony formation assay, and a Boyden chamber assay, respectively.
Protein expression was measured by Western blotting. ATRA reduced cell proliferation, colony formation, and migration/invasion in both wild-type and
gemcitabine-resistant cell lines. PAK1 expression was significantly increased in resistant cells. Cells treated with ATRA showed decreased expression of PAK1, PAK2, PAK4, and α-smooth muscle actin. The combination of ATRA and
gemcitabine synergistically reduced cell growth in both wild-type and
gemcitabine-resistant cell lines. Depletion of PAK1 enhanced ATRA sensitivity in MiaPaCa-2 cells. In conclusion, the antitumor effects of ATRA and its synergism with
gemcitabine are associated with downregulation of PAKs. NEW & NOTEWORTHY The inhibitory effect of
all-trans retinoic acid (ATRA) on cell proliferation, colony formation, and migration/invasion was associated with downregulation of
p21-activated kinases (PAKs), and depletion of PAK1 enhanced ATRA sensitivity in MiaPaCa-2 cells. The combination of ATRA and
gemcitabine synergistically reduced cell growth in both wild-type and
gemcitabine-resistant pancreatic ductal
adenocarcinoma cells. As an important prognostic marker, α-smooth muscle actin also can be downregulated by ATRA in pancreatic ductal
adenocarcinoma cells.