COX-2/sEH Dual Inhibitor PTUPB Suppresses Glioblastoma Growth by Targeting Epidermal Growth Factor Receptor and Hyaluronan Mediated Motility Receptor

Overview

Journal Oncotarget

Specialty Oncology

Date 2017 Nov 21

PMID 29152086

Citations 20

Authors

Junyang Li

Yali Zhou

Handong Wang

Yongyue Gao

Liwen Li

Sung Hee Hwang

Xiangjun Ji

Bruce D Hammock

Affiliations

Soon will be listed here.

Abstract

Aims: Cyclooxygenase-2 (COX-2)/soluble epoxide hydrolase (sEH) dual inhibitor, PTUPB, has been demonstrated to inhibit angiogenesis, primary tumor growth and metastasis. The aim of this study is to investigate the effects of PTUPB on glioblastoma cells and xenograft model.

Results: We show here that PTUPB inhibits glioblastoma cell proliferation and G1 phase cell cycle arrest , and suppresses the tumor growth and angiogenesis . The expression and activation of epidermal growth factor receptor (EGFR) and its downstream kinases, ERK1/2 and AKT, are reduced by PTUPB, indicating that the EGF/EGFR signaling pathway is a potential target. Moreover, PTUPB dramatically suppresses expression of hyaluronan mediated motility receptor (HMMR) in the glioblastoma cell lines and xenograft mouse model, suggesting that the HMMR is the other potential target.

Materials And Methods: Cellular immunofluorescence assays were used for cell staining of actin fibers and HMMR. CCK-8 kit was used for cell proliferation assay. Cell-cycle analysis was performed by flow cytometry. Quantitative real-time PCR assay was performed to test mRNA level. Western blot analysis was used to test protein expression. Immunohistochemical staining assay was used for xenograft tumor tissue staining of Ki-67, CD31 and HMMR. The SPSS version 17.0 software was applied for statistical analysis.

Conclusions: Our data demonstrate that PTUPB is a potential therapeutic agent to treat glioblastomas.

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References

Toole B . Hyaluronan: from extracellular glue to pericellular cue. Nat Rev Cancer. 2004; 4(7):528-39. DOI: 10.1038/nrc1391. View

Dandekar D, Lokeshwar B . Inhibition of cyclooxygenase (COX)-2 expression by Tet-inducible COX-2 antisense cDNA in hormone-refractory prostate cancer significantly slows tumor growth and improves efficacy of chemotherapeutic drugs. Clin Cancer Res. 2004; 10(23):8037-47. DOI: 10.1158/1078-0432.CCR-04-1208. View

Imig J, Hammock B . Soluble epoxide hydrolase as a therapeutic target for cardiovascular diseases. Nat Rev Drug Discov. 2009; 8(10):794-805. PMC: 3021468. DOI: 10.1038/nrd2875. View

Nakamura K, Smyth M . Targeting cancer-related inflammation in the era of immunotherapy. Immunol Cell Biol. 2016; 95(4):325-332. DOI: 10.1038/icb.2016.126. View

Rojas M, Yao S, Lin Y . Controlling epidermal growth factor (EGF)-stimulated Ras activation in intact cells by a cell-permeable peptide mimicking phosphorylated EGF receptor. J Biol Chem. 1996; 271(44):27456-61. DOI: 10.1074/jbc.271.44.27456. View

Pala A, Karpel-Massler G, Kast R, Wirtz C, Halatsch M . Epidermal to Mesenchymal Transition and Failure of EGFR-Targeted Therapy in Glioblastoma. Cancers (Basel). 2013; 4(2):523-30. PMC: 3712701. DOI: 10.3390/cancers4020523. View

Turley E, Noble P, Bourguignon L . Signaling properties of hyaluronan receptors. J Biol Chem. 2001; 277(7):4589-92. DOI: 10.1074/jbc.R100038200. View

Goswami S, Wan D, Yang J, Trindade da Silva C, Morisseau C, Kodani S . Anti-Ulcer Efficacy of Soluble Epoxide Hydrolase Inhibitor TPPU on Diclofenac-Induced Intestinal Ulcers. J Pharmacol Exp Ther. 2016; 357(3):529-36. PMC: 4885505. DOI: 10.1124/jpet.116.232108. View

Zhang G, Panigrahy D, Hwang S, Yang J, Mahakian L, Wettersten H . Dual inhibition of cyclooxygenase-2 and soluble epoxide hydrolase synergistically suppresses primary tumor growth and metastasis. Proc Natl Acad Sci U S A. 2014; 111(30):11127-32. PMC: 4121808. DOI: 10.1073/pnas.1410432111. View

10.

Chi A, Sorensen A, Jain R, Batchelor T . Angiogenesis as a therapeutic target in malignant gliomas. Oncologist. 2009; 14(6):621-36. PMC: 4790121. DOI: 10.1634/theoncologist.2008-0272. View

11.

Hall C, Yang B, Yang X, Zhang S, Turley M, Samuel S . Overexpression of the hyaluronan receptor RHAMM is transforming and is also required for H-ras transformation. Cell. 1995; 82(1):19-26. DOI: 10.1016/0092-8674(95)90048-9. View

12.

Crainie M, Belch A, Mant M, Pilarski L . Overexpression of the receptor for hyaluronan-mediated motility (RHAMM) characterizes the malignant clone in multiple myeloma: identification of three distinct RHAMM variants. Blood. 1999; 93(5):1684-96. View

13.

Booth L, Roberts J, Cruickshanks N, Tavallai S, Webb T, Samuel P . PDE5 inhibitors enhance celecoxib killing in multiple tumor types. J Cell Physiol. 2014; 230(5):1115-27. PMC: 4398314. DOI: 10.1002/jcp.24843. View

14.

Schmelzer K, Inceoglu B, Kubala L, Kim I, Jinks S, Eiserich J . Enhancement of antinociception by coadministration of nonsteroidal anti-inflammatory drugs and soluble epoxide hydrolase inhibitors. Proc Natl Acad Sci U S A. 2006; 103(37):13646-51. PMC: 1564210. DOI: 10.1073/pnas.0605908103. View

15.

Reardon D, Wen P, Mellinghoff I . Targeted molecular therapies against epidermal growth factor receptor: past experiences and challenges. Neuro Oncol. 2014; 16 Suppl 8:viii7-13. PMC: 4207137. DOI: 10.1093/neuonc/nou232. View

16.

Li J, Tang C, Li L, Li R, Fan Y . Quercetin sensitizes glioblastoma to t-AUCB by dual inhibition of Hsp27 and COX-2 in vitro and in vivo. J Exp Clin Cancer Res. 2016; 35:61. PMC: 4818891. DOI: 10.1186/s13046-016-0331-1. View

17.

Philip B, Roland C, Daniluk J, Liu Y, Chatterjee D, Gomez S . A high-fat diet activates oncogenic Kras and COX2 to induce development of pancreatic ductal adenocarcinoma in mice. Gastroenterology. 2013; 145(6):1449-58. PMC: 3873752. DOI: 10.1053/j.gastro.2013.08.018. View

18.

Chinot O, Nishikawa R, Mason W, Henriksson R, Saran F, Cloughesy T . Upfront bevacizumab may extend survival for glioblastoma patients who do not receive second-line therapy: an exploratory analysis of AVAglio. Neuro Oncol. 2016; 18(9):1313-8. PMC: 4999000. DOI: 10.1093/neuonc/now046. View

19.

Wang D, DuBois R . Eicosanoids and cancer. Nat Rev Cancer. 2010; 10(3):181-93. PMC: 2898136. DOI: 10.1038/nrc2809. View

20.

Chinot O, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R . Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014; 370(8):709-22. DOI: 10.1056/NEJMoa1308345. View