Palmitic Acid Methyl Ester Induces G₂/M Arrest in Human Bone Marrow-Derived Mesenchymal Stem Cells via the p53/p21 Pathway

Abstract

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.

Methyl Palmitate—A suitable adjuvant for Sorafenib therapy to reduce in vivo toxicity and to enhance anti‐cancer effects on hepatocellular carcinoma cells

“…MP has induced Peroxisome proliferator‐activated receptor gamma‐α (PPAR‐α) expression for its preventive action on steatohepatitis 68 and the PPAR‐α expression is high in certain organs which are having high level of fatty acid metabolism. MP was found to induce G2/M arrest via p53/p21 pathway 69 and proven to have anti‐inflammatory activity in experimental rat 70 . MP has protected peritoneal cells from toxicity induced in rat by Lipopolysacharide (LPS) by inhibiting the enhanced macrophages 71 .…”

Neferine induces apoptosis by modulating the ROS‑mediated JNK pathway in esophageal squamous cell carcinoma

“…The Cdk1/cyclin B1 complex is a crucial initiator of mitosis, and has been reported to coordinate G 2 /M progression (34). Studies have revealed that activation of this complex can be blocked by upregulating p21 (34,35). In the present study, neferine suppressed proliferation of tumor cells, by blocking cell cycle progression, although the mechanisms underlying this phenomenon are unclear and require further investigation.…”

“…In the present study, it was observed that neferine treatment increased the G 2 /M phase in ESCC cells by downregulating the expression of cyclin B1 while upregulating that of p21. The Cdk1/cyclin B1 complex is a crucial initiator of mitosis, and has been reported to coordinate G 2 /M progression (34). Studies have revealed that activation of this complex can be blocked by upregulating p21 (34,35).…”

Palmitic Acid Methyl Ester Enhances Adipogenic Differentiation in Rat Adipose Tissue-Derived Mesenchymal Stem Cells through a G Protein-Coupled Receptor-Mediated Pathway

“…Liu et al showed that PAME was synthesized through PA methylation via the AdoMet-dependent catechol-O-methyltransferase catalytic pathway in adipocytes [ 37 ]. Recently, we detected PAME in the rat bone marrow [ 25 ]. Lee et al reported that the culture medium of differentiated adipocytes of NIH 3T3 and 3T3-L1 cells contained a significant concentration of PAME [ 17 ].…”

“…PAME has been shown to inhibit phagocytosis [ 38 , 39 ], fibrotic effects [ 18 – 20 ], inflammation [ 21 , 22 ], and oxidative stress [ 40 ]; to induce vasodilation [ 17 , 35 , 36 , 41 , 42 ]; and to prevent nonalcoholic steatohepatitis [ 43 ]. In stem cells, PAME is able to induce cell cycle arrest at the G 2 /M phase in hBM-MSCs [ 25 ]. However, the molecular mechanisms underlying PAME-induced stem cell differentiation are still unclear.…”