The clinical management of glioblastoma is still challenging despite aggressive surgery and radio-chemotherapy approaches. Better understanding of the molecules involved in glioblastoma chemoresistance is necessary to improve the treatment and predict prognosis.
Materials and Methods
We analyzed the expression and possible roles of cytosolic phospholipase A2 alpha (cPLA2α) in human glioblastoma cell lines and patient samples using immunohistochemistry and cellular assays. We analyzed the signaling pathways that cPLA2α regulates in glioblastoma cells using western blot analysis.
Our work demonstrated that cPLA2α is upregulated in glioblastoma compared with normal neuron cells. The expression of cPLA2α varies in multiple glioblastoma cell lines and is associated with chemoresistance rather than tumor development. cPLA2α depletion moderately inhibits glioblastoma growth and survival but remarkably sensitizes chemo-resistant glioblastoma cells to several chemotherapeutic agents. Mechanistically, cPLA2α knockdown significantly suppresses the PI3K/Akt/mTOR pathway in glioblastoma cells.
We are the first to identify the important role of cPLA2α in glioblastoma in response to chemotherapy. Our data also suggest that cPLA2α may serve as a biomarker to indicate prognosis of glioblastoma patients with high level of cPLA2α to chemotherapy.
To read this article in full you will need to make a payment
Purchase one-time access:Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
One-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:Subscribe to The American Journal of the Medical Sciences
Already a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
- Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012.Int J Cancer. 2015; 136: E359-E386
- Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial.Lancet Oncol. 2009; 10: 459-466
- The 2016 World Health Organization classification of tumors of the central nervous system: a summary.Acta Neuropathol. 2016; 131: 803-820
- Antiangiogenesis treatment for glioblastoma multiforme: challenges and opportunities.J Natl Compr Cancer Netw: JNCCN. 2008; 6: 515-522
- Multidrug resistance in glioblastoma stem-like cells: role of the hypoxic microenvironment and adenosine signaling.Mol Asp Med. 2017; 55: 140-151
- Inhibition of MNK pathways enhances cancer cell response to chemotherapy with temozolomide and targeted radionuclide therapy.Cell Signal. 2016; 28: 1412-1421
- Musashi-1 regulates AKT-derived IL-6 autocrinal/paracrinal malignancy and chemoresistance in glioblastoma.Oncotarget. 2016; 7: 42485-42501
- MiR-203 downregulation is responsible for chemoresistance in human glioblastoma by promoting epithelial-mesenchymal transition via.SNAI2 Oncotarget. 2015; 6: 8914-8928
- Phospholipase A2 enzymes: physical structure, biological function, disease implication, chemical inhibition, and therapeutic intervention.Chem Rev. 2011; 111: 6130-6185
- Gelb MH Processive interfacial catalysis by mammalian 85-kilodalton phospholipase A2 enzymes on product-containing vesicles: application to the determination of substrate preferences.Biochemistry. 1993; 32: 5949-5958
- Brain lipid metabolism in the cPLA2 knockout mouse.J Lipid Res. 2003; 44: 109-117
- Cytosolic phospholipase A2: biochemical properties and physiological roles.IUBMB Life. 2006; 58: 328-333
- Induction of cPLA2 in lung epithelial cells and non-small cell lung cancer is mediated by Sp1 and c-Jun.J Biol Chem. 2001; 276: 42737-42743
- Sjolander A Activation of cPLA2 is required for leukotriene D4-induced proliferation in colon cancer cells.Carcinogenesis. 2005; 26: 1988-1998
- Cytosolic phospholipase A2-alpha: a potential therapeutic target for prostate cancer.Clin Cancer Res. 2008; 14: 8070-8079
- Cytosolic phospholipase A2alpha regulates G1 progression through modulating FOXO1 activity.FASEB J. 2016; 30: 1155-1170
- Cytosolic phospholipase A2alpha sustains pAKT, pERK and AR levels in PTEN-null/mutated prostate cancer cells.Biochim Biophys Acta. 2013; 1831: 1146-1157
- Estrogen induces phospholipase A2 activation through ERK1/2 to mobilize intracellular calcium in MCF-7 cells.Steroids. 2006; 71: 256-265
- Blockage of cytosolic phospholipase A2 alpha sensitizes aggressive breast cancer to doxorubicin through suppressing ERK and mTOR kinases.Biochem Biophys Res Commun. 2018; 496: 153-158
- Golgi-associated cPLA2alpha regulates endothelial cell-cell junction integrity by controlling the trafficking of transmembrane junction proteins.Mol Biol Cell. 2009; 20: 4225-4234
- Blenis J ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions.Microbiol Mol Biol Rev. 2004; 68: 320-344
- Stein DG Anti-tumor effects of progesterone in human glioblastoma multiforme: role of PI3K/Akt/mTOR signaling.J Steroid Biochem Mol Biol. 2015; 146: 62-73
- cPLA2alpha activates PI3K/AKT and inhibits Smad2/3 during epithelial-mesenchymal transition of hepatocellular carcinoma cells.Cancer Lett. 2017; 403: 260-270
- Targeting of cytosolic phospholipase A2alpha impedes cell cycle re-entry of quiescent prostate cancer cells.Oncotarget. 2015; 6: 34458-34474
- Cytosolic phospholipase A2 activation correlates with HER2 overexpression and mediates estrogen-dependent breast cancer cell growth.Mol Endocrinol. 2010; 24: 953-968
- Glioblastoma and chemoresistance to alkylating agents: Involvement of apoptosis, autophagy, and unfolded protein response.Pharmacol Ther. 2017; 184: 13-41
- Cytosolic phospholipase A2 as a molecular target for the radiosensitization of ovarian cancer.Cancer Lett. 2011; 304: 137-143
- Inhibitors of phospholipase A2 and their therapeutic potential: an update on patents (2012-2016).Expert Opin Ther Pat. 2017; 27: 217-225
- Loss of PTEN stabilizes the lipid modifying enzyme cytosolic phospholipase A(2)alpha via AKT in prostate cancer cells.Oncotarget. 2014; 5: 6289-6299
- AKT and cytosolic phospholipase A2alpha form a positive loop in prostate cancer cells.Curr Cancer Drug Targets. 2015; 15: 781-791
- Critical role of arachidonic acid-activated mTOR signaling in breast carcinogenesis and angiogenesis.Oncogene. 2013; 32: 160-170
- Arachidonic acid promotes migration and invasion through a PI3K/Akt-dependent pathway in MDA-MB-231 breast cancer cells.Prostaglandins Leukot Essent Fatty Acids. 2014; 90: 169-177
- Arachidonic acid activates phosphatidylinositol 3-kinase signaling and induces gene expression in prostate cancer.Cancer Res. 2006; 66: 1427-1433
Published online: June 25, 2018
Accepted: June 19, 2018
Received: March 10, 2018
This work was supported by grant from the Medicine Project of Hubei Province (H2015026).
The authors have no conflicts of interest to declare.
© 2018 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.