Abstract
Cyclooxygenase-2 (COX-2) is involved in diverse processes such as inflammation, carcinogenesis and apoptosis. As COX-2 inhibitors interfere with these processes, inhibition of COX-2 has been suggested as a promising anticancer treatment. However, the role of COX-2 in modulation of apoptosis as well as the death pathways affected by COX-2 inhibitors are poorly characterized. Here we demonstrate that the selective COX-2 inhibitors NS-398 and nimesulide increased TNF sensitivity of TNF-resistant HeLa H21 and TNF-sensitive HeLa D98 cells, although this cytokine induced significant COX-2 activity, as judged by prostaglandin E2 (PGE2) production, only in H21 cells. TNF did also not induce PGE2 production in MCF-7/casp-3 cells stably expressing COX-2; however, nimesulide strongly enhanced TNF-induced apoptosis in these cells. Furthermore, COX-2 activity in HeLa H21 cells could be inhibited by NS-398 concentrations that were 10 000-fold lower compared to those required for the induction of cell death. Most intriguingly, sensibilization to apoptosis was specifically observed in response to activation of death receptors. Not only TNF-induced cell death but also apoptosis triggered by the CD95 and TRAIL receptors was enhanced by nimesulide. In contrast, apoptosis induced by the anticancer drugs doxorubicine and etoposide that target the mitochondrial death pathway remained unaffected. Together, our data suggest that COX-2 inhibitors overcome apoptosis resistance and selectively sensitize tumor cells to the extrinsic death receptor-induced apoptotic pathway independently of COX-2.
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References
Callejas NA, Casado M, Bosca L and Martin-Sanz P . (2000). Hepatology, 35, 341–348.
Cao Y and Prescott SM . (2002). J. Cell. Physiol., 190, 279–286.
Chang YW, Jakobi R, McGinty A, Foschi M, Dunn MJ and Sorokin A . (2000). Mol Cell. Biol., 20, 8571–8579.
Daniel PT, Wieder T, Sturm I and Schulze-Osthoff K . (2001). Leukemia, 15, 1022–1032.
Dannenberg AJ, Altorki NK, Boyle JO, Dang C, Howe LR, Weksler BB and Subbaramaiah K . (2001). Lancet Oncol., 2, 544–551.
Davies NM, McLachlan AJ, Day RO and Williams KM . (2000). Clin. Pharmacokinet., 38, 225–242.
Dempke W, Rie C, Grothey A and Schmoll HJ . (2001). J. Cancer Res. Clin. Oncol., 127, 411–417.
Desagher S, Osen-Sand A, Montessuit S, Magnenat E, Vilbois F, Hochmann A, Journot L, Antonsson B and Martinou JC . (2001). Mol. Cell, 8, 601–611.
Eberhart CE, Coffey RJ, Radhika A, Giardiello FM, Ferrenbach S and DuBois RN . (1994). Gastroenterology, 107, 1183–1188.
Elder DJ, Halton DE, Hague A and Paraskeva C . (1997). Clin. Cancer Res., 3, 1679–1683.
Elder DJ, Halton DE, Playle LC and Paraskeva C . (2002). Int. J. Cancer, 99, 323–327.
Engels IH, Stepczynska A, Stroh C, Lauber K, Berg C, Schwenzer R, Wajant H, Janicke RU, Porter AG, Belka C, Gregor M, Schulze-Osthoff K and Wesselborg S . (2000). Oncogene, 19, 4563–4573.
Grösch S, Tegeder I, Niederberger E, Bräutigam L and Geisslinger G . (2001). FASEB J., 15, 2742–2744.
Gupta RA and DuBois RN . (2000). Ann. N. Y. Acad. Sci., 10, 196–204.
He Q, Luo X, Huang Y and Sheikh MS . (2002). Oncogene, 21, 6032–6040.
Held J and Schulze-Osthoff K . (2001). Drug Resist. Update, 4, 243–252.
Hida T, Kozaki K, Muramatsu H, Masuda A, Shimizu S, Mitsudomi T, Sugiura T, Ogawa M and Takahashi T . (2000). Clin. Cancer Res., 6, 2006–2011.
Hida T, Yatabe Y, Achiwa H, Muramatsu H, Kozaki K, Nakamura S, Ogawa M, Mitsudomi T, Sugiura T and Takahashi T . (1998). Cancer Res., 58, 3761–3764.
Hsi LC, Baek SJ and Eling TE . (2000). Exp. Cell Res., 256, 563–570.
Hsu AL, Ching TT, Wang DS, Song X, Rangnekar VM and Chen CS . (2000). J. Biol. Chem., 275, 11397–11403.
Huang Y, He Q, Hillman MJ, Rong R and Sheikh MS . (2001). Cancer Res., 61, 6918–6924.
Jänicke RU, Lee FHH and Porter AG . (1994). Mol. Cell. Biol., 14, 5661–5670.
Jänicke RU, Lin XY, Lee FH and Porter AG . (1996). Mol. Cell. Biol., 16, 5245–5253.
Jänicke RU, Sprengart ML, Wati MR and Porter AG . (1998). J. Biol. Chem., 273, 9357–9360.
Jendrossek V, Handrick R and Belka C . (2003). FASEB J. in press.
Jiang XH, Lam SK, Lin MCM, Jiang SH, Kung HF, Slosberg ED, Soh JW, Weinstein IB and Wong BCY . (2002). Oncogene, 21, 6113–6122.
Karin M and Lin A . (2002). Nat. Immunol., 3, 221–227.
Ko Y, Totzke G, Schiermeyer B, Zeitler H, Schmitz U, Vetter H and Sachinidis A . (1995). Mol. Cell. Probes, 9, 215–222.
Lin MT, Lee RC, Yang PC, Ho FM and Kuo ML . (2001). J. Biol. Chem., 276, 48997–49002.
Liu XH, Yao S, Kirschenbaum A and Levine AC . (1998). Cancer Res., 58, 4245–4249.
Masferrer JL, Leahy KM, Koki AT, Zweifel BS, Settle SL, Woerner BM, Edwards DA, Flickinger AG, Moore RJ and Seibert K . (2000). Cancer Res., 60, 1306–1311.
McGinty A, Chang YWE, Sorokin A, Bokemeyer D and Dunn MJ . (2000). J. Biol. Chem., 275, 12095–12101.
Nzeako UC, Guicciardi ME, Yoon JH, Bronk SF and Gores GJ . (2002). Hepatology, 35, 552–559.
Oshima M, Dinchuk JE, Kargman SL, Oshima H, Hancock B, Kwong E, Trzaskos JM, Evans JF and Taketo MM . (1996). Cell, 87, 803–809.
Porter AG and Jänicke RU . (1999). Cell Death Differ., 6, 99–104.
Ravi R and Bedi A . (2002). Cancer Res., 62, 4180–4185.
Ricchi P, Di Matola T, Ruggiero G, Zanzi D, Apicella A, di Palma A, Pensabene M, Pignata S, Zarrilli R and Acquaviva AM . (2002). Br. J. Cancer, 86, 1501–1509.
Ristimäki A, Honkanen N, Jänkälä H, Sipponen P and Härkönen M . (1997). Cancer Res., 57, 1276–1280.
Ruzzene M, Penzo D and Pinna LA . (2002). Biochem. J., 364, 41–47.
Schulze-Osthoff K, Ferrari D, Los M, Wesselborg S and Peter ME . (1998). Eur. J. Biochem., 254, 439–459.
Shureiqi I, Chen D, Lotan R, Yang P, Newman RA, Fischer SM and Lippman SM . (2000). Cancer Res., 60, 6846–6850.
Smith M, Hawcroft G and Hull MA . (2000). Eur. J. Cancer, 36, 664–674.
Song X, Lin HP, Johnson AJ, Tseng PH, Yang YT, Kulp SK and Chen CS . (2002). J. Natl. Cancer Inst., 94, 585–591.
Souza RF, Shewmake K, Beer DG, Cryer B and Spechler SJ . (2000). Cancer Res., 60, 5767–5772.
Steinbach G, Lynch PM, Phillips RK, Wallace MH, Hawk E, Gordon GB, Wakabayashi N, Saunders B, Shen Y, Fujimura T, Su LK and Levin B . (2000). N. Engl. J. Med., 342, 1946–1952.
Stier S, Totzke G, Grünewald E, Neuhaus T, Fronhoffs S, Sachinidis A, Vetter H, Schulze-Osthoff K and Ko Y . (2000). FEBS Lett., 467, 299–304.
Subbaramaiah K, Telang N, Ramonetti JT, Araki R, DeVito B, Weksler BB and Dannenberg AJ . (1996). Cancer Res., 56, 4424–4429.
Taketo MM . (1998). J. Natl. Cancer Inst., 90, 1609–1620.
Tang W, Sun YJ, Half E, Kuo MT and Sinicrope F . (2002). Cancer Res., 62, 4903–4908.
Tegeder I, Pfeilschifter J and Geisslinger G . (2001). FASEB J., 15, 2057–2072.
Thun MJ, Henley SJ and Patrono C . (2002). J. Natl. Cancer Inst., 94, 252–266.
Tucker ON, Dannenberg AJ, Yang FK, Zhang F, Teng LS, Daly JM, Soslow RA, Masferrer JL, Woerner BM, Koki AT and Fahey TJ . (1999). Cancer Res., 59, 987–990.
Walczak H and Krammer PH . (2000). Exp. Cell Res., 256, 58–66.
Waskewich C, Blumenthal RD, Li H, Stein R, Goldenberg DM and Burton J . (2002). Cancer Res., 62, 2029–2033.
Wesselborg S, Engels IH, Rossmann E, Los M and Schulze-Osthoff K . (1999). Blood, 93, 3053–3063.
Wong BC, Jiang XhX, Fan XM, Lin MC, Jiang SH, Lam SK and Kung HF . (2003). Oncogene, 22, 1189–1197.
Zhang X, Morham SG, Langenbach R and Young DA . (1999). J. Exp. Med., 190, 451–459.
Zimmermann KC, Sarbia M, Weber AA, Borchard F, Gabbert HE and Schror K . (1999). Cancer Res., 59, 198–204.
Acknowledgements
We wish to thank H Walczak and TE Eling for providing materials and A Zeipert for excellent technical assistance. This work was supported by the Deutsche Krebshilfe.
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Totzke, G., Schulze-Osthoff, K. & Jänicke, R. Cyclooxygenase-2 (COX-2) inhibitors sensitize tumor cells specifically to death receptor-induced apoptosis independently of COX-2 inhibition. Oncogene 22, 8021–8030 (2003). https://doi.org/10.1038/sj.onc.1206837
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DOI: https://doi.org/10.1038/sj.onc.1206837
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