Potential role of cdk4/6 inhibition- targeted mechanisms as a novel therapeutic strategy in pancreatic cancer cells

The mortality rate of pancreatic cancer has close parallels to its incidence rate because of limited therapeutics and lack of the effective prognosis. Despite various novel chemotherapeutics combinations, the five-year survival rate is still under 6 percent. In this study, we first aimed to investigate the aberrantly activated PI3K/AKT and EMT signaling with the treatment of CDK4/6 inhibitor palbociclib (PD-0332991) in Panc-1 and MiaPaCa-2 pancreatic cancer cells. We secondly aim to determine the role of palbociclib on the regulation of cellular energy metabolism and self-renewal capacity through examining AMPK/mTOR signaling and fatty acid (FA) synthesis by modulation of intracellular miR-33a levels which is a regulator of SREBP in pancreatic cancer cells. We determined that palbociclib effectively reduced the cell viability and proliferation within 24 h and induced cell cycle arrest at the G1 phase by downregulation of aberrant expression of CDK4/6 in both cell lines. PI3K/AKT signalling and EMT process restricted by palbociclib treatment. Palbociclib exerted different effect on the regulation of FA synthesis in each cell line. Palbociclib-induced activation of AMPKα as an energy-sensing target, led to modulation FA synthesis due to upregulation of miR-33a levels in each cell lines. In conclusion, understanding the effect of palbociclib on the aberrantly activated signaling axis may put forward a new therapeutic strategy to reduce the cell viability and metastatic ability of pancreatic cancer. These findings provided that a deeper understanding about possible interactions of cell cycle activity and cellular energy metabolism may facilitate the prevention of self-renewal mechanisms in pancreatic cancer cells.