Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Activation of the Fas pathway independently of Fas ligand during apoptosis induced by camptothecin in p53 mutant human colon carcinoma cells

Abstract

The present study explored the role of the cell surface receptor Fas (CD95/APO-1) in apoptosis induced by camptothecin (CPT) in the HT29 colon carcinoma cell line. CPT-induced apoptosis was associated with high molecular weight DNA fragmentation as measured by filter elution. This fragmentation was inhibited by the caspase inhibitor, z-VAD-fmk and by cycloheximide, which also prevented proteolytic activation of caspase-3 and poly(ADP-ribose)polymerase cleavage. Under such conditions, Fas, Fas ligand, Bax, and p21 expression were increased and Fas recruited the FADD adaptor. Fas expression increase was blocked by cycloheximide but not by z-VAD-fmk, consistent with caspase activation downstream from Fas. Treatment of HT29 cells with FasL or with the CH-11 agonistic anti-Fas antibody potentiated the apoptotic response of cells treated with CPT. The anti-Fas blocking antibody ZB4 and the Fas-ligand inhibitor failed to protect HT29 cells from CPT-induced apoptosis. Such a protection was obtained by transient expression of constructs encoding a dominant-negative mutant of FADD, FADD in an antisense orientation and E8 or MC159 viral proteins that inhibit Fas-induced apoptosis at the level of FADD and procaspase-8, respectively. Together, these data show that topoisomerase I-mediated DNA damage-induced apoptosis involves activation of the Fas pathway without detectable Fas-ligand requirement in CPT-treated cells.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
Figure 4

Similar content being viewed by others

Abbreviations

CPT:

camptothecin

CHX:

cycloheximide

PARP:

poly (ADP-ribose) polymerase.

References

  • Aragane Y, Kulms D, Metze D, Wilkes G, Poppelmann B, Luger TA, Schwarz T . 1998 J. Cell. Biol. 140: 171–182

  • Bertin J, Armstrong RC, Ottilie S, Martin DA, Wang Y, Banks S, Wang GH, Senkevich TG, Alnemri ES, Moss B, Lenardo MJ, Tomaselli KJ, Cohen JI . 1997 Proc. Natl. Acad. Sci. USA 94: 1172–1176

  • Bertrand R, Kohn KW, Solary E, Pommier Y . 1995 Drug Development Res. 34: 138–144

  • Bertrand R, Solary E, O'Connor P, Kohn KW, Pommier Y . 1994 Exp. Cell Res. 211: 314–321

  • Chan FK-M, Chun HJ, Zhen L, Siegel RM, Bui KL, Lenardo MJ . 2000 Science 288: 2351–2354

  • Chen AY, Liu LF . 1994 Annu. Rev. Pharmacol. Toxicol. 94: 194–218

  • Dubrez L, Goldwasser F, Genne P, Pommier Y, Solary E . 1995 Leukemia 9: 1013–1024

  • Eischen CM, Kottke TJ, Martins LM, Basi GS, Tung JS, Earnshaw WC, Leibson PJ, Kaufmann SH . 1997 Blood 90: 935–943

  • Favre-Felix N, Fromentin A, Hammann A, Solary E, Martin F, Bonnotte B . 2000 J. Immunol 164: 5023–5027

  • Friesen C, Herr I, Krammer PH, Debatin KM . 1996 Nat. Med. 2: 574–577

  • Goldwasser F, Bae IS, Torres K, Pommier Y . 1995 Cancer Res. 55: 2116–2121

  • Goldwasser F, Shimizu T, Jackman J, Hoki Y, O'Connor PM, Kohn KW, Pommier Y . 1996 Cancer Res. 56: 4430–4437

  • Gunthert AR, Strater J, von Reyher U, Henne C, Joos S, Koretz K, Moldenhaue RG, Krammer PH, Moller P . 1996 J. Cell. Biol. 134: 1089–1096

  • Houghton JA, Harwood FG, Tillman DM . 1997 Proc. Natl. Acad. Sci. USA 94: 8144–8149

  • Khodarev NN, Sokolova IA, Vaughan AT . 1998 Int. J. Radiat Biol. 73: 455–467

  • Krammer PH, Dhein J, Walczak H, Behrmann I, Mariani S, Matiba B, Fath M, Daniel PT, Knipping E, Westendorp MO . 1994 Immunol Rev. 142: 175–191

  • Kuida K, Lippke JA, Ku G, Harding MW, Livingston DJ, Su MS.-S, Flavell RA . 1995 Science 267: 2000–2006

  • Memon SA, Hou J, Moreno MB, Zacharchuk CM . 1998 J. Immunol 160: 2046–2049

  • Micheau O, Solary E, Hamman A, Dimanche-Boitrel M.-T . 1999 J. Biol. Chem. 274: 7987–7992

  • Micheau O, Solary E, Hammann A, Martin F, Dimanche-Boitrel MT . 1997 J. Natl. Cancer 89: 783–789

  • Miyashita T, Reed JC . 1995 Cell 80: 293–299

  • Moller P, Koretz K, Leithauser F, Bruderlein S, Henne C, Quentmeier A, Krammer PH . 1994 Int. J. Cancer 57: 371–377

  • Muzio M, Chinnaiyan AM, Kischkel FC, O'Rourke K, Shevchenko A, Ni J, Scaffidi C, Bretz JD, Zhang M, Gentz R, Mann M, Krammer PH, Peter ME, Dixit VM . 1996 Cell 85: 817–827

  • Nagata S, Golstein P . 1995 Science 267: 1449–1456

  • Nicholson DW, Ali A, Thornberry NA, Vaillancourt JP, Ding CK, Gallant M, Gareau Y, Griffin PR, Labelle M, Lazebnik Y, Munday NA, Raju SM, Smulson ME, Yamin T.-T, Yu V, Miller DK . 1995 Nature 376: 37–43

  • O'Connell J, O'Sullivan GC, Collins JK, Shanahan F . 1996 J. Exp. Med. 184: 1075–1082

  • O'Connor PM, Nieves-Neira W, Kerrigan D, Bertrand R, Goldman J, Kohn KW, Pommier Y . 1991 Cancer Commun. 3: 233–240

  • O'Connor PM, Jackman J, Bae I, Myers TG, Fan S, Mutoh M, Scudiero DA, Monks A, Sausville EA, Weinstein JN, Friend S, Fornace Jr AJ, Kohn KW . 1997 Cancer Res. 57: 4285–4300

  • Oberhammer FA, Hochegger K, Froschl G, Tiefenbacher R, Pavelka M . 1994 J. Cell Biol. 126: 827–837

  • Owen-Schaub LB, Zhang W, Cusack JC, Angelo LS, Santee SM, Fujiwara T, Roth JA, Deisseroth AB, Zhan WW, Kruzel E, Radinsky R . 1995 Mol. Cell. Biol. 15: 3032–3040

  • Pommier Y, Pourquier P, Fan Y, Strumberg D . 1998 Biochim. Biophys. Acta 1400: 83–105

  • Rodrigues NR, Rowan A, Smith MEF, Kerr IB, Bodmer WF, Gannon JV, Lane DP . 1990 Proc. Natl. Acad. Sci. USA 87: 7555–7559

  • Rusnak JM, Calmels TP, Hoyt DG, Kondo Y, Yalowich JC, Lazo JS . 1996 Mol. Pharmacol. 49: 244–252

  • Shao R.-G, Cao C.-X, Zhang H, Kohn KW, Wold MS, Pommier Y . 1999 EMBO J. 18: 1397–1406

  • Shao RG, Cao CX, Shimizu T, O'Connor PM, Kohn KW, Pommier Y . 1997a Cancer Res. 57: 4029–4035

  • Shao RG, Shimizu T, Pommier Y . 1996 Exp. Cell Res. 227: 190–196

  • Shao RG, Shimizu T, Pommier Y . 1997b Exp. Cell Res. 234: 388–397

  • Shimizu T, O'Connor PM, Kohn KW, Pommier Y . 1995 Cancer Res. 55: 228–231

  • Siegel RM, Frederiksen JK, Zacharias DA, Chan FK-M, Johnson M, Lynch D, Tsien RY, Lenardo MJ . 2000 Science 288: 2345–2357

  • Strumberg D, Pilon AA, Smith M, Hickey R, Malkas L, Pommier Y . 2000 Mol. Cell Biol. 20: 3977–3987

  • Tanaka M, Suda T, Haze K, Nakamura N, Sato K, Kimura F, Motoyosh IK, Mizuke M, Tagawa S, Ohga S, Hatake K, Drummond AH, Nagata S . 1996 Nat. Med. 2: 317–322

  • Tillman DM, Harwood FG, Gibson AA, Houghton JA . 1998 Cell Death Differ. 5: 450–457

  • Villunger A, Egle A, Kos M, Hartmann BL, Geley S, Kofler R, Greil R . 1997 Cancer Res. 57: 3331–3334

  • Zhan Q, El-Deiry W, Bae I, Alamo Jr I, Kastan MB, Vogelstein B, Fornace JAJ . 1995 Int. J. Oncol. 6: 937–946

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shao, RG., Cao, CX., Nieves-Neira, W. et al. Activation of the Fas pathway independently of Fas ligand during apoptosis induced by camptothecin in p53 mutant human colon carcinoma cells. Oncogene 20, 1852–1859 (2001). https://doi.org/10.1038/sj.onc.1204264

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1204264

Keywords

This article is cited by

Search

Quick links