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Novel target for induction of apoptosis by cyclo-oxygenase-2 inhibitor SC-236 through a protein kinase C-β1-dependent pathway

Oncogene volume 21, pages 6113–6122 (2002)Cite this article

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of gastrointestinal cancers. Recently, a similar protective effect has been demonstrated by the specific cyclo-oxygenase-2 (COX-2) inhibitors. However, the exact mechanism that accounts for the anti-proliferative effect of specific COX-2 inhibitors is still not fully understood, and it is still controversial whether these protective effects are predominantly mediated through the inhibition of COX-2 activity and prostaglandin synthesis. Identification of molecular targets regulated by COX-2 inhibitors could lead to a better understanding of their pro-apoptotic and anti-neoplastic activities. In the present study, we investigated the effect and the possible molecular target of a COX-2-specific inhibitor SC-236 on gastric cancer. We showed that SC-236 induced apoptosis in gastric cancer cells. However, this effect was not dependent on COX-2 inhibition. SC-236 down-regulated the protein expression and kinase activity of PKC-β1, increased the expression of PKCδ and PKCη, but did not alter the expression of other PKC isoforms in AGS cells. Moreover, exogenous prostaglandins or PGE2 receptor antagonists could not reverse the inhibition effect on PKCβ1 by SC-236, which suggested that this effect occurred through a mechanism independent of cyclo-oxygenase activity and prostaglandin synthesis. Overexpression of PKCβ1 attenuated the apoptotic response of AGS cells to SC-236 and was associated with overexpression of p21waf1/cip1. Inhibition of PKCβ1-mediated overexpression of p21waf1/cip1 partially reduced the anti-apoptotic effect of PKCβ1. The down-regulation of PKCβ1 provides an explanation for COX-independent apoptotic effects of specific COX-2 inhibitor in cultured gastric cancer cells. We also suggest that PKCβ1 act as survival mediator in gastric cancer, and its down-regulation by COX-2 inhibitor SC-236 may provide new target for future treatment of gastric cancer.

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Abbreviations

NSAIDs:

nonsteroidal antiinflammatory drugs

COX:

cyclooxygenase

PKC:

protein kinase C

TPA:

12-0-tetradecanoylphorbol-13-acetate

FBS:

fetal bovine serum

NF-κB:

nuclear factor-κB

PPAR:

peroxisome proliferator activated receptors

References

  • Akashi M, Osawa Y, Koeffler HP, Hachiya M . 1999 Biochem. J. 337: 607–616

  • Barnes CJ, Cameron IL, Hardman WE, Lee M . 1998 Br. J. Cancer 77: 573–580

  • Beier F, Taylor AC, LuValle P . 1999 J. Biol. Chem. 274: 30273–30279

  • Cao Y, Pearman AT, Zimmerman GA, McIntyre TM, Prescott SM . 2000 Proc. Natl. Acad. Sci. USA 97: 11280–11285

  • Cesaro P, Raiteri E, Demoz M, Castino R, Baccino FM, Bonelli G, Isidoro C . 2001 Int. J. Cancer 93: 179–184

  • Das D, Pintucci G, Stern A . 2000 FEBS Lett. 472: 50–52

  • Deacon EM, Pongracz J, Griffiths G, Lord JM . 1997 J. Clin. Pathol. 50: 124–131

  • Dubois RN, Smalley WE . 1996 J. Gastroenterol. 31: 898–906

  • Elder D, Halton DE, Hague A, Paraskeva C . 1997 Clin. Cancer Res. 3: 1679–1683

  • Frey MR, Saxon ML, Zhao X, Rollins A, Evans SS, Black JD . 1997 J. Biol. Chem. 272: 9424–9435

  • Goldberg Y, Nassif II, Pittas A, Tsai LL, Dynlacht BD, Rigas B, Shiff SJ . 1996 Oncogene 12: 893–901

  • Grosch S, Tegeder I, Neiderberger E, Brautigam L, Geisslinger G . 2001 FASEB J. 15: 2742–2744

  • Gupta RA, DuBois RN . 1998 Gastroenterology 114: 1095–1098

  • Hanif R, Pittas A, Feng Y, Koutsos MI, Qiao L, Staiano-Caico L, Shiff SI, Rigas B . 1996 Biochem. Pharmacol. 52: 237–245

  • He TC, Chan TA, Vogelstein B, Kinzler KW . 1999 Cell 99: 335–345

  • Hsu AL, Ching TT, Wang DS, Song X, Rangnekar VM, Chen CS . 2000 J. Biol. Chem. 275: 11397–11403

  • Hug H, Sarre TF . 1993 Biochem. J. 291: 329–343

  • Inoue H, Yokoyama C, Hara S, Tone Y, Tanabe T . 1995 Curr. Opin. Cell Biol. 270: 24965–24971

  • Jaken S . 1996 Curr. Opin. Cell Biol. 8: 168–173

  • Jones DA, Carlton DP, Mcintyre TM, Zimmerman GA, Prescott SM . 1993 Curr. Opin. Cell Biol. 268: 9049–9054

  • Jones MK, Wang H, Peskar BM, Levin E, Itani RM, Sarfeh IJ, Tarnawski AS . 1999 Nat. Med. 5: 1418–1423

  • Jun CD, Oh DC, Kwak HJ, Pae HO, Yoo JC, Choi BM, Chun JS, Park RK, Chung HT . 1997 J. Immunol. 162: 3395–3402

  • Kargman SL, O'Neill GP, Vichers PJ, Evans JF, Mancini JA, Jothy S . 1995 Cancer Res. 55: 3785–3789

  • Kawamori T, Rao CV, Seibert K, Reddy BS . 1998 Cancer Res. 58: 409–412

  • Kinoshita T, Takahashi Y, Sakashita T, Inoue H, Tanabe T, Yoshimoto T . 1999 Biochim. Biophys. Acta 1438: 120–130

  • Kolch W, Heidecker G, Kochs G, Hummel R, Vahidi H, Mischak H, Finkenzeller G, Marme D, Rapp UR . 1993 Nature 364: 249–252

  • Kunikata T, Araki H, Takeeda M, Kato S, Takeuchi K . 2001 J. Physiol. Paris 95: 157–163

  • Li Y, Davis KL, Sytkowski AJ . 1999 J. Biol. Chem. 271: 27025–27030

  • Li M, Wu XY, Xu XC . 2001 Cancer Res. 7: 1010–1016

  • Livneh E, Shimon T, Bechor E, Doki Y, Schieren I, Weinstein IB . 1998 Oncogene 12: 1545–1555

  • Mitchell JA, Warner TD . 1999 Br. J. Pharmacol. 128: 1121–1132

  • Nishizuka Y . 1988 Nature (Lond) 334: 661–665

  • Nishizuka Y . 1992 Science (Wash. DC) 258: 607–614

  • Reddy BS, Rao CV, Seibert K . 1996 Cancer Res. 56: 4566–4569

  • Richter M, Weiss M, Weinberger I, Fürstenberger G, Marian B . 2001 Carcinogenesis 22: 17–25

  • Ristimaki A, Honkanen N, Jankala H, Sipponen P, Harkonen M . 1997 Cancer Res. 57: 1276–1281

  • Sawaoka H, Kawano S, Tsuji S, Tsuji M, Gunawan ES, Takei Y, Nagano K, Hori M . 1998 Am. J. Physiol. 274: G1061–G1065

  • Schwartz GK, Friedman A, Dhupar SK, Ehleiter D, Maslak P, Lai L, Loganzo F, Kelsen DP, Fuks Z, Albino AP . 1995 J. Natl. Cancer Inst. 87: 1394–1399

  • Schwartz GK, Jiang J, Kelsen D, Albino AP . 1993 J. Natl. Cancer Inst. 85: 402–407

  • Shao J, Fujiwara T, Kadowaki Y, Fukazawa T, Waku T, Itoshima T, Yamatsuji T, Nishizaki M, Roth JA, Tanaka N . 2000 Oncogene 19: 726–736

  • Sheng H, Shao J, Morrow JD, Beauchamp RD, DuBois RN . 1998 Cancer Res. 58: 362–366

  • Shiff SJ, Qiao L, Tsai LL, Rigas B . 1995 J. Clin. Invest. 96: 491–503

  • Shureiqi I, Chen D, Lee JJ, Yang P, Newman RA, Brenner DE, Lotan R, Fischer SM, Lippman SM . 2000 J. Natl. Cancer Inst. (Bethesda) 92: 1136–1142

  • Simmons D, Levy DB, Yannoni Y, Erikson RL . 1989 Proc. Natl. Acad. Sci. USA 86: 1178–1182

  • Steinbach G, Lynch PM, Phillips RK, Wallace MH, Hawk E, Gordon GB, Wakabayashi N, Saunders B, Shen Y, Fujimura T, Su LK, Levin B, Godio L, Patterson S, Rodriguez-Bigas MA, Jester SL, King KL, Schumacher M, Abbruzzese J, DuBois RN, Hittelman WN, Zimmerman S, Sherman JW, Kelloff G . 2000 N. Engl. J. Med. 342: 1946–1952

  • Subbaramaiah K, Telang N, Ramnetti JT, Araki R, DeVito B, Weksler BB, Danenberg AJ . 1996 Cancer Res. 56: 4424–4429

  • Sugibayashi R, Shimizu T, Suzuki T, Yamamoto N, Hamada H, Takeda K . 2001 Oncogene 20: 1220–1228

  • Teicher BA, Menon K, Alvarez E, Galbreath E, Shih C, Faul MM . 2001a Anticancer Res. 21: 3175–3184

  • Teicher BA, Menon K, Alvarez E, Liu P, Shih C, Faul MM . 2001b In Vivo 15: 185–193

  • Teicher BA, Menon K, Alvarez E, Galbreath E, Shih C, Faul MM . 2001c Anticancer Res. 21: 3175–3184

  • Teicher BA, Menon K, Alvarez E, Galbreath E, Shih C, Faul MM . 2001d Cancer Chemother. Pharmacol. 48: 473–480

  • Thun MJ . 1996 Gastroenterol. Clin. North Am. 25: 333–348

  • Tsujii M, DuBois RN . 1995 Cell 83: 493–501

  • Tsujii M, Kawano S, DuBois RN . 1997 Proc. Natl. Acad. Sci. USA 94: 3336–3340

  • Tsujii M, Kawano S, Tsuji S, Sawaoka H, Hori M, DuBois RN . 1998 Cell 93: 705–716

  • Tucker ON, Dannenberg AJ, Yang FK, Zhang F, Teng LA, Daly JM, Soslow RA, Masferer JL, Woerner BM, Koki AT, Fahey TJ . 1999 Cancer Res. 59: 987–991

  • Weber CK, Liptay S, Wirth T, Adler G, Schmid RM . 2000 Gastroenterology 119: 1209–1218

  • Williams C, Luongo D, Radhika A, Zhang T, Lamps LW, Nanney LB, Beauchamp RD, Dubois RN . 1996 Gastroenterology 111: 1134–1140

  • Williams CS, Tsujii M, Reese J, Dey SK, DuBois RN . 2000 J. Clin. Invest. 105: 1589–1594

  • Wilson KT, Fu S, Ramanujam KS, Meltzer SJ . 1998 Cancer Res. 58: 2929–2934

  • Won JS, Suh HW, Kim YH, Song D, Huh S, Lee JK, Lee KJ . 1998 Mol. Brain Res. 60: 203–214

  • Yasui W, Sumiyoshi H, Ochiai A, Tahara E . 1985 Jpn. J. Cancer Res. 76: 1168–1173

  • Zeng YX, el-Deiry WS . 1996 Oncogene 12: 1557–1564

  • Zhang X, Morham SG, Langenbach R, Young DA . 1999 J. Exp. Med. 190: 451–460

  • Zhu GH, Wong BCY, Eggo MC, Yuen ST, Lai KC, Lam SK . 1999a Dig. Dis. Sci. 44: 2020–2026

  • Zhu GH, Wong BCY, Eggo MC, Ching CK, Yuen ST, Chan YET, Lai KC, Lam SK . 1999b Br. J. Cancer 79: 393–400

  • Zhu GH, Wong BCY, Slosberg ED, Eggo MC, Ching CK, Yuen ST, Lai KC, Soh JW, Weinstein IB, Lam SK . 2000 Gastroenterology 118: 507–514

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Acknowledgements

This study is supported by Research Grant Council earmarked research grant HKU7010/99M, and HKU7309/01M of the Hong Kong Special Administrative Region to BCY Wong, and the Gastroenterological Research Fund, University of Hong Kong.

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Authors and Affiliations

  1. Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong

    Shiu-Kum Lam & Benjamin Chun-Yu Wong

  2. Department of Gastroenterology, Rui-jin Hospital, Shanghai, PR China

    Xiao-Hua Jiang & Shi-Hu Jiang

  3. Institute of Molecular Biology, The University of Hong Kong, Hong Kong

    Marie CM Lin & Hsiang-Fu Kung

  4. Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, 10032, New York, NY, USA

    Eric D Slosberg, Jae Won Soh & I Bernard Weinstein

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  1. Xiao-Hua Jiang
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Correspondence to Benjamin Chun-Yu Wong.

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Jiang, XH., Lam, SK., Lin, M. et al. Novel target for induction of apoptosis by cyclo-oxygenase-2 inhibitor SC-236 through a protein kinase C-β1-dependent pathway. Oncogene 21, 6113–6122 (2002). https://doi.org/10.1038/sj.onc.1205778

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