PTEN over-expression by resveratrol in acute lymphoblastic leukemia cells along with suppression of AKT/PKB and ERK1/2 in genotoxic stress

Abstract

The bioactive components of dietary phytochemicals are in the spotlight of research institutes, due to their significant antioxidant activities and health-promoting properties. Resveratrol is a polyphenol which is found abundantly in grapes and berries and has long been known as a chemo-preventive agent. The main purpose of this study was to provide a new mechanistic insight into the growth inhibition of acute lymphoblastic leukemia cells by resveratrol along with a DNA damage agent. It was found that the treatment of pre-B ALL cells by resveratrol in the presence or absence of doxorubicin resulted in decreased cell viability and a synergistic increase in cytotoxicity. Cell death was accompanied by a significant increase in phosphorylated p53 at serine 15 and accumulation of PTEN. In addition, resveratrol inhibited the over-expression of p-AKT and p-ERK1/2. These findings clearly demonstrated that resveratrol and doxorubicin synergistically increase the cytotoxicity of pre-B ALL cells via the hyper-activation of two important tumor suppressor proteins and two major signal transduction pathways.

The Effect of Resveratrol on Cell Viability in the Burkitt’s Lymphoma Cell Line Ramos

“…Here we show that RSV reduces proliferation and cell viability in Ramos cells ( Figure 1 ), concomitant with the induction of caspase-3 and PARP fragmentation ( Figure 2 ), which are normally associate with apoptotic cell death. These results are consistent with previous studies demonstrating that RSV promotes cell growth inhibition in NALM-6 cells [ 36 ]; induces cytotoxicity in human Burkitt’s lymphoma, Raji, and Daudi cell lines [ 40 ]; and also induces cell-cycle arrest in germinal center-like LY1 and LY18 human diffuse large B-cell lymphomas (DLBCLs) [ 15 , 17 ]. Also, in mantle cell lymphomas (MCL), specifically in jeko-1 cell line, resveratrol induces apoptosis modulating several key molecules involve in cell cycle and apoptosis [ 41 ].…”

“…In the case of lymphomas, Jazirehi et al, reported that RSV downregulates two anti-apoptotic proteins, Bcl-XL and Mcl-1, whereas it upregulates the pro-apoptotic proteins Bax and Apaf-1 in the Burkitt’s lymphoma cell line Ramos [ 35 ]. RSV also promotes cell growth inhibition in NALM-6 cells [ 36 ] and blunts PI-3K signaling and glucose metabolism in germinal center-like LY1 and LY18 human diffuse large B-cell lymphomas (DLBCLs) [ 17 ]. However, the molecular mechanisms of action of RSV in lymphoma cells remain largely unknown.…”

Cellular and Molecular Targets of Resveratrol on Lymphoma and Leukemia Cells

“…In a model of ALL, RSV affects the post-translational modifications of p53. RSV increases p53 phosphorylation at serine15 residue and hyper-activates Phosphatase and tensin homolog (PTEN), a tumor suppressor that negatively regulates the protein kinase B (Akt/PKB) signaling pathways [ 75 ].…”

Complete inhibition of phosphatase and tensin homolog promotes the normal and oxygen-glucose deprivation/reperfusion-injured PC12 cells to cell death

“… 20 , 21 Up-regulation of PTEN is capable to inhibit AKT activation by degradation of PI3P to PIP2 16 , 21 and facilitates the p38 MAPK signaling pathway. 22 , 23 Decreasing PTEN activity through phosphorylation of PTEN 24 or deleting of one copy of its gene increases resistance to apoptotic cell death. 25 Hence, down-regulation of PTEN may lead to a neuroprotective effect in the neurodegenerative disorders with a beneficiary role in I/R injury.…”