PTEN status switches cell fate between premature senescence and apoptosis in glioma exposed to ionizing radiation

Abstract

Loss of the tumor suppressor phosphatase and tensin homolog (PTEN) has frequently been observed in human gliomas, conferring AKT activation and resistance to ionizing radiation (IR) and drug treatments. Recent reports have shown that PTEN loss or AKT activation induces premature senescence, but many details regarding this effect remain obscure. In this study, we tested whether the status of PTEN determined fate of the cell by examining PTEN-deficient U87, U251, and U373, and PTEN-proficient LN18 and LN428 glioma cells after exposure to IR. These cells exhibited different cellular responses, senescence or apoptosis, depending on the PTEN status. We further observed that PTEN-deficient U87 cells with high levels of both AKT activation and intracellular reactive oxygen species (ROS) underwent senescence, whereas PTEN-proficient LN18 cells entered apoptosis. ROS were indispensable for inducing senescence in PTEN-deficient cells, but not for apoptosis in PTENproficient cells. Furthermore, transfection with wild-type (wt) PTEN or AKT small interfering RNA induced a change from premature senescence to apoptosis and depletion of p53 or p21 prevented IR-induced premature senescence in U87 cells. Our data indicate that PTEN acts as a pivotal determinant of cell fate, regarding senescence and apoptosis in IR-exposed glioma cells. We conclude that premature senescence could have a compensatory role for apoptosis in the absence of the tumor suppressor PTEN through the AKT/ROS/p53/p21 signaling pathway.

Senescence associated secretory phenotype profile from primary lung mice fibroblasts depends on the senescence induction stimuli

“…Various pathways have been proposed to explain senescence induction; the most studied is replicative senescence due to telomere shortening (Cristofalo et al 2004;Rodier et al 2009Rodier et al , 2010, along with other prematureinduced senescence provoked by diverse stimuli such as oxidative stress and radiation exposure (Toussaint et al 2000;López-Diazguerrero et al 2006;Lee et al 2011), autophagy impairment (Kang et al 2011;Fujii et al 2012), proteasome inhibition (Torres et al 2006;Bitto et al 2010), and oncogenic stress (Bartkova et al 2006). Fig.…”

Heparan sulfation is essential for the prevention of cellular senescence

“…However, cancer cells can be readily induced to undergo premature senescence by the hyperactivation of oncogenes, the loss of tumor suppressors, and a variety of stresses in vitro and in vivo. [44][45][46][47] To our knowledge, no study has elucidated the importance of sulfation status in the regulation of cellular senescence, although tremendous attention has been paid to the role of sulfated PGs in a variety of other biological processes. Here, we demonstrate that the undersulfation of HSPGs, in particular desulfation at the 2-O position of iduronate in HS, prematurely induces cellular senescence through augmented FGFR signaling pathway.…”

MiR-205 determines the radioresistance of human nasopharyngeal carcinoma by directly targeting PTEN

“…Also, PTEN is reportedly involved in the complex response to IR via inducing cell cycle G 2 /M arrest and apoptosis and in sensitizing cells to radiochemotherapy. 15,16 Accordingly, we hypothesized that PTEN is responsible for radioresistance mediated by miR-205. To address this hypothesis, we analyzed PTEN protein and mRNA level in the miR-205-overexpressing CNE-2 cell (CNE-2/miR-205), using CNE-2/vector as a control.…”