NS‑398 promotes pancreatic cancer cell invasion by CD147 and MMP‑2 via the activation of P38

Liu,Hua; Xu,Xuan‑Fu; Zhao,Yan; Tang,Mao‑Chun; Zhou,Ying‑Qun; Gao,Feng‑Hou

doi:10.3892/mmr.2016.4783

NS‑398 promotes pancreatic cancer cell invasion by CD147 and MMP‑2 via the activation of P38

Authors:
- Hua Liu
- Xuan‑Fu Xu
- Yan Zhao
- Mao‑Chun Tang
- Ying‑Qun Zhou
- Feng‑Hou Gao
View Affiliations

Affiliations: Department of Gastroenterology, The Tenth Hospital Affiliated to Tongji University, Shanghai 200072, P.R. China, Institute of Oncology, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, P.R. China
Published online on: January 14, 2016 https://doi.org/10.3892/mmr.2016.4783
Pages: 2208-2214

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The overexpression or abnormal activation of cyclo‑oxygenase‑2 (COX‑2) has been reported in pancreatic cancer cells. NS‑398, a selective inhibitor of COX‑2, is unable to inhibit pancreatic cancer cell proliferation, as determined by a Cell Counting Kit 8 assay. However, it does increase cancer cell invasiveness, and therefore the invasiveness of the PANC‑1 cells was determined, along with the activation of P38, which was assessed by western blotting. In the present study, to evaluate the mechanisms underlying the action of NS‑398 in pancreatic cancer cells, PANC‑1 cells were treated with NS‑398, and the invasion signaling pathways of cluster of differentiation (CD)147‑matrix metalloproteinase (MMP)‑2 and mitogen‑activated protein kinases were evaluated. The results showed that NS‑398‑induced the expression of CD147 and MMP‑2 via the activation of P38, which was involved in antiproliferative activity and induced pancreatic cancer cell invasiveness. The PANC‑1 cells were also co‑treated with CD147 small interfering (si)RNA and NS‑398, and it was found that the NS‑398‑induced activation of P38 was not inhibited by CD147 siRNA, however, the expression of MMP‑2 was inhibited. CD147 siRNA inhibited the invasiveness of the pancreatic cancer cells induced by NS‑398, but also restored NS‑398‑induced antiproliferative activity. These data indicated that P38 in the pancreatic cancer cells was non‑specifically activated by NS‑398. This activation induced the expression of CD147‑MMP‑2, opposed the antiproliferative activity of NS‑398 and increased the invasiveness of the PANC‑1 cells.

View Figures

View References

1	Nentwich MF, Bockhorn M, König A, Izbicki JR and Cataldegirmen G: Surgery for advanced and metastatic pancreatic cancer-current state and trends. Anticancer Res. 32:1999–2002. 2012.PubMed/NCBI
2	Fidler IJ: Origin and biology of cancer metastasis. Cytometry. 10:673–680. 1989. View Article : Google Scholar : PubMed/NCBI
3	Liotta LA, Steeg PS and Stetler-Stevenson WG: Cancer metastasis and angiogenesis: An imbalance of positive and negative regulation. Cell. 64:327–336. 1991. View Article : Google Scholar : PubMed/NCBI
4	Hanahan D and Weinberg RA: Hallmarks of cancer: The next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI
5	Walsh N, O'Donovan N, Kennedy S, Henry M, Meleady P, Clynes M and Dowling P: Identification of pancreatic cancer invasion-related proteins by proteomic analysis. Proteome Sci. 7:32009. View Article : Google Scholar : PubMed/NCBI
6	Ramer R, Weinzierl U, Schwind B, Brune K and Hinz B: Ceramide is involved in r(+)-methanandamide-induced cyclooxygenase-2 expression in human neuroglioma cells. Mol Pharmacol. 64:1189–1198. 2003. View Article : Google Scholar : PubMed/NCBI
7	Mollace V, Muscoli C, Masini E, Cuzzocrea S and Salvemini D: Modulation of prostaglandin biosynthesis by nitric oxide and nitric oxide donors. Pharmacol Rev. 57:217–252. 2005. View Article : Google Scholar : PubMed/NCBI
8	Pereira C, Sousa H, Silva J, Brandão C, Elgueta-Karstegl C, Farrell PJ, Medeiros R and Dinis-Ribeiro M: The −1195G allele increases the transcriptional activity of cyclooxygenase-2 gene (COX-2) in colon cancer cell lines. Mol Carcinog. 53(Suppl 1): E92–E95. 2014. View Article : Google Scholar
9	Wójcik M, Ramadori P, Blaschke M, Sultan S, Khan S, Malik IA, Naz N, Martius G, Ramadori G and Schultze FC: Immunodetection of cyclooxygenase-2 (COX-2) is restricted to tissue macrophages in normal rat liver and to recruited mono-nuclear phagocytes in liver injury and cholangiocarcinoma. Histochem Cell Biol. 137:217–233. 2012. View Article : Google Scholar
10	Young AL, Chalmers CR, Hawcroft G, Perry SL, Treanor D, Toogood GJ, Toogood GJ, Jones PF and Hull MA: Regional differences in prostaglandin E₂ metabolism in human colorectal cancer liver metastases. BMC Cancer. 13:922013. View Article : Google Scholar
11	Shibata-Kobayashi S, Yamashita H, Okuma K, Shiraishi K, Igaki H, Ohtomo K and Nakagawa K: Correlation among 16 biological factors [p53, p21(waf1), MIB-1 (Ki-67), p16 (INK4A), cyclin D1, E-cadherin, Bcl-2, TNF-α, NF-κB, TGF-β, MMP-7, COX-2, EGFR, HER2/neu, ER and HIF-1α] and clinical outcomes following curative chemoradiation therapy in 10 patients with esophageal squamous cell carcinoma. Oncol Lett. 5:903–910. 2013.PubMed/NCBI
12	Yan WF, Sun PC, Nie CF and Wu G: Cyclooxygenase-2 polymorphisms were associated with the risk of gastric cancer: Evidence from a meta-analysis based on case-control studies. Tumour Biol. 34:3323–3330. 2013. View Article : Google Scholar : PubMed/NCBI
13	Hillion J, Smail SS, Di Cello F, Belton A, Shah SN, Huso T, Schuldenfrei A, Nelson DM, Cope L, Campbell N, et al: The HMGA1-COX-2 axis: A key molecular pathway and potential target in pancreatic adenocarcinoma. Pancreatology. 12:372–379. 2012. View Article : Google Scholar : PubMed/NCBI
14	Okami J, Nakamori S, Hiraoka N, Tsujie M, Hayashi N, Yamamoto H, Fujiwara Y, Nagano H, Dono K, Umeshita K, et al: Suppression of pancreatic cancer cell invasion by a cycloox-ygenase-2-specific inhibitor. Clin Exp Metastasis. 20:577–584. 2003. View Article : Google Scholar
15	Duan DP, Dang XQ, Wang KZ, Wang YP, Zhang H and You WL: The cyclooxygenase-2 inhibitor NS-398 inhibits proliferation and induces apoptosis in human osteosarcoma cells via downregulation of the survivin pathway. Oncol Rep. 28:1693–1700. 2012.PubMed/NCBI
16	Youns M, Efferth T and Hoheisel JD: Transcript profiling identifies novel key players mediating the growth inhibitory effect of NS-398 on human pancreatic cancer cells. Eur J Pharmacol. 650:170–177. 2011. View Article : Google Scholar
17	Araki E, Forster C, Dubinsky JM, Ross ME and Iadecola C: Cyclooxygenase-2 inhibitor ns-398 protects neuronal cultures from lipopolysaccharide-induced neurotoxicity. Stroke. 32:2370–2375. 2001. View Article : Google Scholar : PubMed/NCBI
18	Kumar S, Boehm J and Lee JC: p38 MAP kinases: Key signalling molecules as therapeutic targets for inflammatory diseases. Nat Rev Drug Discov. 2:717–726. 2003. View Article : Google Scholar : PubMed/NCBI
19	Chen X, Lin J, Kanekura T, Su J, Lin W, Xie H, Wu Y, Li J, Chen M and Chang J: A small interfering CD147-targeting RNA inhibited the proliferation, invasiveness and metastatic activity of malignant melanoma. Cancer Res. 66:11323–11330. 2006. View Article : Google Scholar : PubMed/NCBI
20	Yoshida S, Ujiki M, Ding XZ, Pelham C, Talamonti MS, Bell RH Jr, Denham W and Adrian TE: Pancreatic stellate cells (PSCs) express cyclooxygenase-2 (COX-2) and pancreatic cancer stimulates COX-2 in PSCs. Mol Cancer. 4:272005. View Article : Google Scholar : PubMed/NCBI
21	Yip-Schneider MT, Barnard DS, Billings SD, Cheng L, Heilman DK, Lin A, Marshall SJ, Crowell PL, Marshall MS and Sweeney CJ: Cyclooxygenase-2 expression in human pancreatic adenocarcinomas. Carcinogenesis. 21:139–146. 2000. View Article : Google Scholar : PubMed/NCBI
22	Molina MA, Sitja-Arnau M, Lemoine MG, Frazier ML and Sinicrope FA: Increased cyclooxygenase-2 expression in human pancreatic carcinomas and cell lines: Growth inhibition by nonsteroidal anti-inflammatory drugs. Cancer Res. 59:4356–4362. 1999.PubMed/NCBI
23	Tucker ON, Dannenberg AJ, Yang EK, Zhang F, Teng L, Daly JM, Soslow RA, Masferrer JL, Woerner BM, Koki AT and Fahey TJ III: Cyclooxygenase-2 expression is up-regulated in human pancreatic cancer. Cancer Res. 59:987–990. 1999.PubMed/NCBI
24	Wang X, Liang Y, Wang J and Wang M: Effect of NS-398, a cyclooxygenase-2 selective inhibitor, on the cytotoxicity of cytotoxic T lymphocytes to ovarian carcinoma cells. Tumour Biol. 34:1517–1522. 2013. View Article : Google Scholar : PubMed/NCBI
25	Honjo S, Osaki M, Ardyanto TD, Hiramatsu T, Maeta N and Ito H: COX-2 inhibitor, NS398, enhances Fas-mediated apoptosis via modulation of the PTEN-Akt pathway in human gastric carcinoma cell lines. DNA Cell Biol. 24:141–147. 2005. View Article : Google Scholar : PubMed/NCBI
26	Banu N, Buda A, Chell S, Elder D, Moorghen M, Paraskeva C, Qualtrough D and Pignatelli M: Inhibition of COX-2 with NS-398 decreases colon cancer cell motility through blocking epidermal growth factor receptor transactivation: Possibilities for combination therapy. Cell Prolif. 40:768–779. 2007. View Article : Google Scholar : PubMed/NCBI
27	Elder DJ, Halton DE, Playle LC and Paraskeva C: The MEK/ERK pathway mediates COX-2-selective NSAID-induced apoptosis and induced COX-2 protein expression in colorectal carcinoma cells. Int J Cancer. 99:323–327. 2002. View Article : Google Scholar : PubMed/NCBI
28	Yurchenko V, Constant S and Bukrinsky M: Dealing with the family: CD147 interactions with cyclophilins. Immunology. 117:301–309. 2006. View Article : Google Scholar : PubMed/NCBI
29	Yurchenko V, Constant S, Eisenmesser E and Bukrinsky M: Cyclophilin-CD147 interactions: A new target for anti-inflammatory therapeutics. Clin Exp Immunol. 160:305–317. 2010. View Article : Google Scholar : PubMed/NCBI
30	Gabison EE, Hoang-Xuan T, Mauviel A and Menashi S: EMMPRIN/CD147, an MMP modulator in cancer, development and tissue repair. Biochimie. 87:361–368. 2005. View Article : Google Scholar : PubMed/NCBI
31	Yang Y, Lu N, Zhou J, Chen ZN and Zhu P: Cyclophilin A up-regulates MMP-9 expression and adhesion of monocytes/macrophages via CD147 signalling pathway in rheumatoid arthritis. Rheumatology (Oxford). 47:1299–1310. 2008. View Article : Google Scholar
32	Tang Y, Nakada MT, Rafferty P, Laraio J, McCabe FL, Millar H, Cunningham M, Snyder LA, Bugelski P and Yan L: Regulation of vascular endothelial growth factor expression by EMMPRIN via the PI3K-Akt signaling pathway. Mol Cancer Res. 4:371–377. 2006. View Article : Google Scholar : PubMed/NCBI
33	Nabeshima K, Iwasaki H, Koga K, Hojo H, Suzumiya J and Kikuchi M: Emmprin (basigin/CD147): Matrix metalloproteinase modulator and multifunctional cell recognition molecule that plays a critical role in cancer progression. Pathol Int. 56:359–367. 2006. View Article : Google Scholar : PubMed/NCBI
34	Sun J and Hemler ME: Regulation of MMP-1 and MMP-2 production through CD147/extracellular matrix metalloproteinase inducer interactions. Cancer Res. 61:2276–2281. 2001.PubMed/NCBI
35	Kanekura T, Chen X and Kanzaki T: Basigin (CD147) is expressed on melanoma cells and induces tumor cell invasion by stimulating production of matrix metalloproteinases by fibroblasts. Int J Cancer. 99:520–528. 2002. View Article : Google Scholar : PubMed/NCBI
36	Kolli-Bouhafs K, Boukhari A, Abusnina A, Velot E, Gies JP, Lugnier C and Rondé P: Thymoquinone reduces migration and invasion of human glioblastoma cells associated with FAK, MMP-2 and MMP-9 downregulation. Invest New Drugs. 30:2121–2131. 2012. View Article : Google Scholar