Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 2000 Jun;82(11):1827–1834. doi: 10.1054/bjoc.2000.1149

Activation of SAPK/JNK by camptothecin sensitizes androgen-independent prostate cancer cells to Fas-induced apoptosis

A P Costa-Pereira 1,1, S L McKenna 1,2, T G Cotter 1
PMCID: PMC2363235  PMID: 10839298

Abstract

We have previously shown that the androgen-independent prostate cancer cells DU145, despite expressing Fas and FasL, were resistant to anti-Fas-induced apoptosis, and that this resistance could be overcome by pretreating the cells with sublethal doses of camptothecin. Here, we provide evidence that SAPK/JNK activity is required for camptothecin sensitization to anti-Fas-induced apoptosis. Camptothecin, but not Fas ligation, was shown to activate SAPK/JNK in a time-dependent manner, and to induce c-Jun expression. The effects were more prominent in cells treated with both camptothecin and anti-Fas. The expression levels of MKP-1, a phosphatase which regulates SAPK/JNK and which has been implicated in prostate cancer resistance to apoptosis, remained unchanged. Inhibition of caspases had no effect on the SAPK/JNK activation, suggesting that this activation is an upstream event in the Fas-signalling pathway, and is independent of caspase activity. Antisense oligonucleotides targeted to JNK1 and JNK2 reversed the effect of camptothecin. These results suggest that stress kinase activation can significantly influence the fate of androgen-independent prostate cancer cells following Fas receptor ligation. © 2000 Cancer Research Campaign

Keywords: prostate cancer, apoptosis, Fas, camptothecin, SAPK/JNK

Full Text

The Full Text of this article is available as a PDF (376.9 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bost F., McKay R., Dean N., Mercola D. The JUN kinase/stress-activated protein kinase pathway is required for epidermal growth factor stimulation of growth of human A549 lung carcinoma cells. J Biol Chem. 1997 Dec 26;272(52):33422–33429. doi: 10.1074/jbc.272.52.33422. [DOI] [PubMed] [Google Scholar]
  2. Chang H. Y., Nishitoh H., Yang X., Ichijo H., Baltimore D. Activation of apoptosis signal-regulating kinase 1 (ASK1) by the adapter protein Daxx. Science. 1998 Sep 18;281(5384):1860–1863. doi: 10.1126/science.281.5384.1860. [DOI] [PubMed] [Google Scholar]
  3. Costa-Pereira A. P., Cotter T. G. Camptothecin sensitizes androgen-independent prostate cancer cells to anti-Fas-induced apoptosis. Br J Cancer. 1999 May;80(3-4):371–378. doi: 10.1038/sj.bjc.6690365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Dhanasekaran N., Premkumar Reddy E. Signaling by dual specificity kinases. Oncogene. 1998 Sep 17;17(11 REVIEWS):1447–1455. doi: 10.1038/sj.onc.1202251. [DOI] [PubMed] [Google Scholar]
  5. Eischen C. M., Leibson P. J. The Fas pathway in apoptosis. Adv Pharmacol. 1997;41:107–132. doi: 10.1016/s1054-3589(08)61056-x. [DOI] [PubMed] [Google Scholar]
  6. Enari M., Talanian R. V., Wong W. W., Nagata S. Sequential activation of ICE-like and CPP32-like proteases during Fas-mediated apoptosis. Nature. 1996 Apr 25;380(6576):723–726. doi: 10.1038/380723a0. [DOI] [PubMed] [Google Scholar]
  7. Finch A., Holland P., Cooper J., Saklatvala J., Kracht M. Selective activation of JNK/SAPK by interleukin-1 in rabbit liver is mediated by MKK7. FEBS Lett. 1997 Nov 24;418(1-2):144–148. doi: 10.1016/s0014-5793(97)01364-1. [DOI] [PubMed] [Google Scholar]
  8. Frost P. J., Belldegrun A., Bonavida B. Sensitization of immunoresistant prostate carcinoma cell lines to Fas/Fas ligand-mediated killing by cytotoxic lymphocytes: independence of de novo protein synthesis. Prostate. 1999 Sep 15;41(1):20–30. doi: 10.1002/(sici)1097-0045(19990915)41:1<20::aid-pros4>3.0.co;2-w. [DOI] [PubMed] [Google Scholar]
  9. Furuya Y., Isaacs J. T. Differential gene regulation during programmed death (apoptosis) versus proliferation of prostatic glandular cells induced by androgen manipulation. Endocrinology. 1993 Dec;133(6):2660–2666. doi: 10.1210/endo.133.6.8243289. [DOI] [PubMed] [Google Scholar]
  10. Goillot E., Raingeaud J., Ranger A., Tepper R. I., Davis R. J., Harlow E., Sanchez I. Mitogen-activated protein kinase-mediated Fas apoptotic signaling pathway. Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):3302–3307. doi: 10.1073/pnas.94.7.3302. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Griffith T. S., Brunner T., Fletcher S. M., Green D. R., Ferguson T. A. Fas ligand-induced apoptosis as a mechanism of immune privilege. Science. 1995 Nov 17;270(5239):1189–1192. doi: 10.1126/science.270.5239.1189. [DOI] [PubMed] [Google Scholar]
  12. Gupta S., Campbell D., Dérijard B., Davis R. J. Transcription factor ATF2 regulation by the JNK signal transduction pathway. Science. 1995 Jan 20;267(5196):389–393. doi: 10.1126/science.7824938. [DOI] [PubMed] [Google Scholar]
  13. Haldar S., Chintapalli J., Croce C. M. Taxol induces bcl-2 phosphorylation and death of prostate cancer cells. Cancer Res. 1996 Mar 15;56(6):1253–1255. [PubMed] [Google Scholar]
  14. Ham J., Babij C., Whitfield J., Pfarr C. M., Lallemand D., Yaniv M., Rubin L. L. A c-Jun dominant negative mutant protects sympathetic neurons against programmed cell death. Neuron. 1995 May;14(5):927–939. doi: 10.1016/0896-6273(95)90331-3. [DOI] [PubMed] [Google Scholar]
  15. Hazzalin C. A., Le Panse R., Cano E., Mahadevan L. C. Anisomycin selectively desensitizes signalling components involved in stress kinase activation and fos and jun induction. Mol Cell Biol. 1998 Apr;18(4):1844–1854. doi: 10.1128/mcb.18.4.1844. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hedlund T. E., Duke R. C., Schleicher M. S., Miller G. J. Fas-mediated apoptosis in seven human prostate cancer cell lines: correlation with tumor stage. Prostate. 1998 Jul 1;36(2):92–101. doi: 10.1002/(sici)1097-0045(19980701)36:2<92::aid-pros4>3.0.co;2-g. [DOI] [PubMed] [Google Scholar]
  17. Hsiang Y. H., Lihou M. G., Liu L. F. Arrest of replication forks by drug-stabilized topoisomerase I-DNA cleavable complexes as a mechanism of cell killing by camptothecin. Cancer Res. 1989 Sep 15;49(18):5077–5082. [PubMed] [Google Scholar]
  18. Juo P., Kuo C. J., Reynolds S. E., Konz R. F., Raingeaud J., Davis R. J., Biemann H. P., Blenis J. Fas activation of the p38 mitogen-activated protein kinase signalling pathway requires ICE/CED-3 family proteases. Mol Cell Biol. 1997 Jan;17(1):24–35. doi: 10.1128/mcb.17.1.24. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Juo P., Kuo C. J., Yuan J., Blenis J. Essential requirement for caspase-8/FLICE in the initiation of the Fas-induced apoptotic cascade. Curr Biol. 1998 Sep 10;8(18):1001–1008. doi: 10.1016/s0960-9822(07)00420-4. [DOI] [PubMed] [Google Scholar]
  20. Kastan M. B., Onyekwere O., Sidransky D., Vogelstein B., Craig R. W. Participation of p53 protein in the cellular response to DNA damage. Cancer Res. 1991 Dec 1;51(23 Pt 1):6304–6311. [PubMed] [Google Scholar]
  21. Krajewska M., Krajewski S., Epstein J. I., Shabaik A., Sauvageot J., Song K., Kitada S., Reed J. C. Immunohistochemical analysis of bcl-2, bax, bcl-X, and mcl-1 expression in prostate cancers. Am J Pathol. 1996 May;148(5):1567–1576. [PMC free article] [PubMed] [Google Scholar]
  22. Kuerbitz S. J., Plunkett B. S., Walsh W. V., Kastan M. B. Wild-type p53 is a cell cycle checkpoint determinant following irradiation. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7491–7495. doi: 10.1073/pnas.89.16.7491. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kyriakis J. M., Banerjee P., Nikolakaki E., Dai T., Rubie E. A., Ahmad M. F., Avruch J., Woodgett J. R. The stress-activated protein kinase subfamily of c-Jun kinases. Nature. 1994 May 12;369(6476):156–160. doi: 10.1038/369156a0. [DOI] [PubMed] [Google Scholar]
  24. Lenczowski J. M., Dominguez L., Eder A. M., King L. B., Zacharchuk C. M., Ashwell J. D. Lack of a role for Jun kinase and AP-1 in Fas-induced apoptosis. Mol Cell Biol. 1997 Jan;17(1):170–181. doi: 10.1128/mcb.17.1.170. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Leppä S., Saffrich R., Ansorge W., Bohmann D. Differential regulation of c-Jun by ERK and JNK during PC12 cell differentiation. EMBO J. 1998 Aug 3;17(15):4404–4413. doi: 10.1093/emboj/17.15.4404. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Longthorne V. L., Williams G. T. Caspase activity is required for commitment to Fas-mediated apoptosis. EMBO J. 1997 Jul 1;16(13):3805–3812. doi: 10.1093/emboj/16.13.3805. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Magi-Galluzzi C., Mishra R., Fiorentino M., Montironi R., Yao H., Capodieci P., Wishnow K., Kaplan I., Stork P. J., Loda M. Mitogen-activated protein kinase phosphatase 1 is overexpressed in prostate cancers and is inversely related to apoptosis. Lab Invest. 1997 Jan;76(1):37–51. [PubMed] [Google Scholar]
  28. Magi-Galluzzi C., Montironi R., Cangi M. G., Wishnow K., Loda M. Mitogen-activated protein kinases and apoptosis in PIN. Virchows Arch. 1998 May;432(5):407–413. doi: 10.1007/s004280050184. [DOI] [PubMed] [Google Scholar]
  29. Maundrell K., Antonsson B., Magnenat E., Camps M., Muda M., Chabert C., Gillieron C., Boschert U., Vial-Knecht E., Martinou J. C. Bcl-2 undergoes phosphorylation by c-Jun N-terminal kinase/stress-activated protein kinases in the presence of the constitutively active GTP-binding protein Rac1. J Biol Chem. 1997 Oct 3;272(40):25238–25242. doi: 10.1074/jbc.272.40.25238. [DOI] [PubMed] [Google Scholar]
  30. O'Connell J., O'Sullivan G. C., Collins J. K., Shanahan F. The Fas counterattack: Fas-mediated T cell killing by colon cancer cells expressing Fas ligand. J Exp Med. 1996 Sep 1;184(3):1075–1082. doi: 10.1084/jem.184.3.1075. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Oehm A., Behrmann I., Falk W., Pawlita M., Maier G., Klas C., Li-Weber M., Richards S., Dhein J., Trauth B. C. Purification and molecular cloning of the APO-1 cell surface antigen, a member of the tumor necrosis factor/nerve growth factor receptor superfamily. Sequence identity with the Fas antigen. J Biol Chem. 1992 May 25;267(15):10709–10715. [PubMed] [Google Scholar]
  32. Park J., Kim I., Oh Y. J., Lee K., Han P. L., Choi E. J. Activation of c-Jun N-terminal kinase antagonizes an anti-apoptotic action of Bcl-2. J Biol Chem. 1997 Jul 4;272(27):16725–16728. doi: 10.1074/jbc.272.27.16725. [DOI] [PubMed] [Google Scholar]
  33. Rokhlin O. W., Glover R. A., Cohen M. B. Fas-mediated apoptosis in human prostatic carcinoma cell lines occurs via activation of caspase-8 and caspase-7. Cancer Res. 1998 Dec 15;58(24):5870–5875. [PubMed] [Google Scholar]
  34. Smeal T., Binetruy B., Mercola D. A., Birrer M., Karin M. Oncogenic and transcriptional cooperation with Ha-Ras requires phosphorylation of c-Jun on serines 63 and 73. Nature. 1991 Dec 12;354(6353):494–496. doi: 10.1038/354494a0. [DOI] [PubMed] [Google Scholar]
  35. Sánchez-Perez I., Murguía J. R., Perona R. Cisplatin induces a persistent activation of JNK that is related to cell death. Oncogene. 1998 Jan 29;16(4):533–540. doi: 10.1038/sj.onc.1201578. [DOI] [PubMed] [Google Scholar]
  36. Teng D. H., Perry W. L., 3rd, Hogan J. K., Baumgard M., Bell R., Berry S., Davis T., Frank D., Frye C., Hattier T. Human mitogen-activated protein kinase kinase 4 as a candidate tumor suppressor. Cancer Res. 1997 Oct 1;57(19):4177–4182. [PubMed] [Google Scholar]
  37. Toyoshima F., Moriguchi T., Nishida E. Fas induces cytoplasmic apoptotic responses and activation of the MKK7-JNK/SAPK and MKK6-p38 pathways independent of CPP32-like proteases. J Cell Biol. 1997 Nov 17;139(4):1005–1015. doi: 10.1083/jcb.139.4.1005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Uslu R., Borsellino N., Frost P., Gárban H., Ng C. P., Mizutani Y., Belldegrun A., Bonavida B. Chemosensitization of human prostate carcinoma cell lines to anti-fas-mediated cytotoxicity and apoptosis. Clin Cancer Res. 1997 Jun;3(6):963–972. [PubMed] [Google Scholar]
  39. Villunger A., Egle A., Marschitz I., Kos M., Böck G., Ludwig H., Geley S., Kofler R., Greil R. Constitutive expression of Fas (Apo-1/CD95) ligand on multiple myeloma cells: a potential mechanism of tumor-induced suppression of immune surveillance. Blood. 1997 Jul 1;90(1):12–20. [PubMed] [Google Scholar]
  40. Wyllie A. H., Kerr J. F., Currie A. R. Cell death: the significance of apoptosis. Int Rev Cytol. 1980;68:251–306. doi: 10.1016/s0074-7696(08)62312-8. [DOI] [PubMed] [Google Scholar]
  41. Xu S., Cobb M. H. MEKK1 binds directly to the c-Jun N-terminal kinases/stress-activated protein kinases. J Biol Chem. 1997 Dec 19;272(51):32056–32060. doi: 10.1074/jbc.272.51.32056. [DOI] [PubMed] [Google Scholar]
  42. Yamamoto K., Ichijo H., Korsmeyer S. J. BCL-2 is phosphorylated and inactivated by an ASK1/Jun N-terminal protein kinase pathway normally activated at G(2)/M. Mol Cell Biol. 1999 Dec;19(12):8469–8478. doi: 10.1128/mcb.19.12.8469. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Yonehara S., Ishii A., Yonehara M. A cell-killing monoclonal antibody (anti-Fas) to a cell surface antigen co-downregulated with the receptor of tumor necrosis factor. J Exp Med. 1989 May 1;169(5):1747–1756. doi: 10.1084/jem.169.5.1747. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Yoshida B. A., Dubauskas Z., Chekmareva M. A., Christiano T. R., Stadler W. M., Rinker-Schaeffer C. W. Mitogen-activated protein kinase kinase 4/stress-activated protein/Erk kinase 1 (MKK4/SEK1), a prostate cancer metastasis suppressor gene encoded by human chromosome 17. Cancer Res. 1999 Nov 1;59(21):5483–5487. [PubMed] [Google Scholar]
  45. de Souza P. L., Cooper M. R., Imondi A. R., Myers C. E. 9-Aminocamptothecin: a topoisomerase I inhibitor with preclinical activity in prostate cancer. Clin Cancer Res. 1997 Feb;3(2):287–294. [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES