The apoptosis-resistance in t -AUCB-treated glioblastoma cells depends on activation of Hsp27
- PDF / 577,874 Bytes
- 8 Pages / 595.276 x 790.866 pts Page_size
- 9 Downloads / 150 Views
LABORATORY INVESTIGATION
The apoptosis-resistance in t-AUCB-treated glioblastoma cells depends on activation of Hsp27 Junyang Li • Weixing Hu • Qing Lan
Received: 6 July 2012 / Accepted: 8 August 2012 Ó Springer Science+Business Media, LLC. 2012
Abstract We previously reported that sEH inhibitor t-AUCB suppresses the growth of human glioblastoma U251 and U87 cell lines and induces cell-cycle G0/G1 phase arrest. In present study, we found even 96 h-treatment of 200 lM t-AUCB can not induce apoptosis in U251 and U87 cells. We also revealed that 200 lM t-AUCB significantly elevates the activation of p38 MAPK, MAPKAPK2 and Hsp27. The p38 MAPK inhibitor SB203580 and the inhibitor of Hsp27 phosphorylation, KRIBB3, were used to investigate the mechanism of the apoptosis-resistance. The results showed that, after blocking the activation of Hsp27 by SB203580 or KRIBB3, 200 lM t-AUCB significantly induces apoptosis and increases caspase-3 activities in U251 and U87 cells. Our data demonstrated that t-AUCB induces cell apoptosis after blocking itself-induced activation of Hsp27, and that the activation of Hsp27 may confer chemoresistance in GBM cells. The combination of t-AUCB and the inhibitor of Hsp27 phosphorylation may be a potential strategy for treatment of glioblastoma. Keywords Soluble epoxide hydrolase Inhibitor Glioma Chemotherapy Resistance Heat shock protein 27
J. Li Q. Lan (&) Department of Neurosurgery, Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou 215004, Jiangsu, China e-mail: [email protected]
Introduction Soluble epoxide hydrolase (sEH) in mammalian is a ubiquitously expressed homodimeric enzyme, principally hydrolyzing epoxyeicosatrienoic acids (EETs) which are converted from arachidonic acid by cytochrome P450 (CYP450) enzymes [1]. EETs possess numerous beneficial effects on inflammatory and cardiovascular events. sEH converts EETs to dihydroxyeicosatrienoic acids, reduces the activity of EETs. Thus, sEH and its inhibitors are well studied in inflammatory and cardiovascular diseases [2, 3]. The effects of sEH inhibitors on tumor diseases are seldom investigated and still unclear [4]. Recently, we revealed that one of the improved sEH inhibitors, trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB) [5, 6], suppresses human glioblastoma cell lines U251 and U87 growth by activating NF-jB-p65 and induces cell-cycle G0/G1 phase arrest by regulating Cyclin D1 and CDC2 [7]. To further investigate the effects of t-AUCB on glioblastomas and related mechanisms, in present study, we demonstrate that U251 and U87 cells resist t-AUCB-induced apoptosis, and the resistance depends on the activation of Hsp27. Hsp27 is a member of the heat shock protein family. It regulates apoptosis through interaction with key components of apoptotic signaling pathways [8]. The activation of Hsp27 was reported to confer resistance to cisplatin and gemcitabine in lung cancer stemlike cells [9]. Herein we revealed that the activation of Hsp27 also confer chemoresistance to
Data Loading...
