Palbociclib, a selective CDK4/6 inhibitor, restricts cell survival and epithelial‐mesenchymal transition in Panc‐1 and MiaPaCa‐2 pancreatic cancer cells
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Abstract
The mortality rate of pancreatic cancer has close parallels to its incidence rate
because of limited therapeutics and lack of effective prognosis. Despite various novel
chemotherapeutics combinations, the 5-year survival rate is still under 5%. In the
current study, we aimed to modulate the aberrantly activated PI3K/AKT pathway and
epithelial-mesenchymal transition (EMT) signaling with the treatment of CDK4/6 inhibitor
PD-0332991 (palbociclib) in Panc-1 and MiaPaCa-2 pancreatic cancer cells. It was found
that PD-0332991 effectively reduced cell viability and proliferation dose-dependently
within 24 hours. In addition, PD-0332991 induced cell cycle arrest at the G1 phase
by downregulation of aberrant expression of CDK4/6 through the dephosphorylation of
Rb in each cell lines. Although PD-0332991 treatment increased epithelial markers
and decreased mesenchymal markers, the nuclear translocation of β-catenin was not
prevented by PD-0332991 treatment, especially in MiaPaCa-2 cells. Effects of PD-0332991
on the regulation of PI3K/AKT signaling and its downstream targets such as GSK-3 were
cell type-dependent. Although the activity of AKT was inhibited in both cell lines,
the phosphorylation of GSK-3β at Ser9 increased only in Panc-1. In conclusion, PD-0332991
induced cell cycle arrest and reduced the cell viability of Panc-1 and MiaPaCa-2 cells.
However, PD-0332991 differentially affects the regulation of the PI3K/AKT pathway
and EMT process in cells due to its distinct influence on Rb and GSK-3/β-catenin signaling.
Understanding the effect of PD-0332991 on the aberrantly activated signaling axis
may put forward a new therapeutic strategy to reduce the cell viability and metastatic
process of pancreatic cancer.