Palmitic Acid Methyl Ester Induces G2M Arrest in Human Bone Marrow-Derived Mesenchymal Stem Cells via the p53p21 Pathway

الملخص EN

Bone marrow-derived mesenchymal cells (BM-MSCs) are able to differentiate into adipocytes, which can secrete adipokines to affect BM-MSC proliferation and differentiation.

Recent evidences indicated that adipocytes can secrete fatty acid metabolites, such as palmitic acid methyl ester (PAME), which is able to cause vasorelaxation and exerts anti-inflammatory effects.

However, effects of PAME on BM-MSC proliferation remain unclear.

The aim of this study was to investigate the effect of PAME on human BM-MSC (hBM-MSC) proliferation and its underlying molecular mechanisms.

hBM-MSCs were treated with PAME for 48 h and then subjected to various analyses.

The results from the present study show that PAME significantly reduced the levels of G2/M phase regulatory proteins, cyclin-dependent kinase 1 (Cdk1), and cyclin B1 and inhibited proliferation in hBM-MSCs.

Moreover, the level of Mdm2 protein decreased, while the levels of p21 and p53 protein increased in the PAME-treated hBM-MSCs.

However, PAME treatment did not significantly affect apoptosis/necrosis, ROS generation, and the level of Cdc25C protein.

PAME also induced intracellular acidosis and increased intracellular Ca2+ levels.

Cotreatment with PAME and Na+/H+ exchanger inhibitors together further reduced the intracellular pH but did not affect the PAME-induced decreases of cell proliferation and increases of the cell population at the G2/M phase.

Cotreatment with PAME and a calcium chelator together inhibited the PAME-increased intracellular Ca2+ levels but did not affect the PAME-induced cell proliferation inhibition and G2/M cell cycle arrest.

Moreover, the half-life of p53 protein was prolonged in the PAME-treated hBM-MSCs.

Taken together, these results suggest that PAME induced p53 stabilization, which in turn increased the levels of p53/p21 proteins and decreased the levels of Cdk1/cyclin B1 proteins, thereby preventing the activation of Cdk1, and eventually caused cell cycle arrest at the G2/M phase.

The findings from the present study might help get insight into the physiological roles of PAME in regulating hBM-MSC proliferation.