Palbociclib, a selective CDK4/6 inhibitor, restricts cell survival and epithelial‐mesenchymal transition in Panc‐1 and MiaPaCa‐2 pancreatic cancer cells

Autor: Elif Damla Arisan, Dilek Telci, Pınar Obakan Yerlikaya, Ozge Rencuzogullari, Ajda Çoker Gürkan
Rok vydání: 2019
Předmět:
0301 basic medicine
Epithelial-Mesenchymal Transition
Cell cycle checkpoint
Pyridines
Cell
Apoptosis
Palbociclib
Biochemistry
Piperazines
Phosphatidylinositol 3-Kinases
03 medical and health sciences
0302 clinical medicine
Pancreatic cancer
Biomarkers
Tumor
Tumor Cells
Cultured
medicine
Humans
Epithelial–mesenchymal transition
Viability assay
Phosphorylation
Protein Kinase Inhibitors
Molecular Biology
Protein kinase B
beta Catenin
PI3K/AKT/mTOR pathway
Cell Proliferation
Glycogen Synthase Kinase 3 beta
Chemistry
Cyclin-Dependent Kinase 4
Cell Cycle Checkpoints
Cyclin-Dependent Kinase 6
Cell Biology
medicine.disease
Gene Expression Regulation
Neoplastic
Pancreatic Neoplasms
030104 developmental biology
medicine.anatomical_structure
030220 oncology & carcinogenesis
Cancer research
Proto-Oncogene Proteins c-akt
Signal Transduction
Zdroj: Journal of Cellular Biochemistry. 121:508-523
ISSN: 1097-4644
0730-2312
Popis: 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.
Databáze: OpenAIRE
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