Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 2001 Sep 1;85(9):1403–1411. doi: 10.1054/bjoc.2001.2107

Differential effect of vinorelbine versus paclitaxel on ERK2 kinase activity during apoptosis in MCF-7 cells

X M Liu 1, L G Wang 1, W Kreis 1, D R Budman 1, L M Adams 2
PMCID: PMC2375254  PMID: 11720482

Abstract

The effects of vinorelbine and paclitaxel on the activity of extracellular signal-regulated protein kinase2 (ERK2), a member of MAP kinase, and its role in the induction of bcl-2 phosphorylation and apoptosis were evaluated in MCF-7 cells. We demonstrated that ERK2 was activated rapidly by vinorelbine, and was inhibited by either paclitaxel or estramustine. A 3-fold increase of ERK2 kinase activity was observed within 30 min when MCF-7 cells were treated with 0.1 μM vinorelbine. In contrast, the same treatment with paclitaxel resulted in a significant decrease of ERK2 kinase activity. We also demonstrated that elevated bcl-2 phosphorylation induced by vinorelbine is paralleled by decrease of a complex formation between bcl-2 and bax, cleavage of poly (ADP) ribose polymerase (PARP) protein, activation of caspase-7, and apoptosis. The levels of bcl-2 phosphorylation, bax, and PARP were not significantly affected by 2′-amino-3′-methoxyflavone (PD 98059), an ERK kinase specific inhibitor. Thus, our data suggest that the apoptosis induced by vinorelbine in MCF-7 cells is mediated through the bcl-2 phosphorylation/bax/caspases pathways, and that activation of ERK2 by vinorelbine does not directly lead to the drug-mediated apoptosis. Since decrease of PARP occurred quickly following the treatment of MCF-7 cells with either 0.1 μM of vinorelbine or paclitaxel, this protein may serve as an early indicator of apoptosis induced not only by DNA damaging agents, but also by antimicrotubule drugs.   http://www.bjcancer.com © 2001 Cancer Research Campaign

Keywords: vinorelbine, MAP kinase, ERK2, apoptosis, bcl-2 phosphorylation, poly (ADP) ribose polymerase

Full Text

The Full Text of this article is available as a PDF (146.1 KB).

Selected References

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

  1. Alessi D. R., Cuenda A., Cohen P., Dudley D. T., Saltiel A. R. PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo. J Biol Chem. 1995 Nov 17;270(46):27489–27494. doi: 10.1074/jbc.270.46.27489. [DOI] [PubMed] [Google Scholar]
  2. Attalla H., Westberg J. A., Andersson L. C., Adlercreutz H., Mäkelä T. P. 2-Methoxyestradiol-induced phosphorylation of Bcl-2: uncoupling from JNK/SAPK activation. Biochem Biophys Res Commun. 1998 Jun 29;247(3):616–619. doi: 10.1006/bbrc.1998.8870. [DOI] [PubMed] [Google Scholar]
  3. Avruch J., Zhang X. F., Kyriakis J. M. Raf meets Ras: completing the framework of a signal transduction pathway. Trends Biochem Sci. 1994 Jul;19(7):279–283. doi: 10.1016/0968-0004(94)90005-1. [DOI] [PubMed] [Google Scholar]
  4. Basu A., Haldar S. Microtubule-damaging drugs triggered bcl2 phosphorylation-requirement of phosphorylation on both serine-70 and serine-87 residues of bcl2 protein. Int J Oncol. 1998 Oct;13(4):659–664. doi: 10.3892/ijo.13.4.659. [DOI] [PubMed] [Google Scholar]
  5. Blagosklonny M. V., Bishop P. C., Robey R., Fojo T., Bates S. E. Loss of cell cycle control allows selective microtubule-active drug-induced Bcl-2 phosphorylation and cytotoxicity in autonomous cancer cells. Cancer Res. 2000 Jul 1;60(13):3425–3428. [PubMed] [Google Scholar]
  6. Blagosklonny M. V., Giannakakou P., el-Deiry W. S., Kingston D. G., Higgs P. I., Neckers L., Fojo T. Raf-1/bcl-2 phosphorylation: a step from microtubule damage to cell death. Cancer Res. 1997 Jan 1;57(1):130–135. [PubMed] [Google Scholar]
  7. Blagosklonny M. V., Schulte T. W., Nguyen P., Mimnaugh E. G., Trepel J., Neckers L. Taxol induction of p21WAF1 and p53 requires c-raf-1. Cancer Res. 1995 Oct 15;55(20):4623–4626. [PubMed] [Google Scholar]
  8. Blagosklonny M. V., Schulte T., Nguyen P., Trepel J., Neckers L. M. Taxol-induced apoptosis and phosphorylation of Bcl-2 protein involves c-Raf-1 and represents a novel c-Raf-1 signal transduction pathway. Cancer Res. 1996 Apr 15;56(8):1851–1854. [PubMed] [Google Scholar]
  9. Boise L. H., González-García M., Postema C. E., Ding L., Lindsten T., Turka L. A., Mao X., Nuñez G., Thompson C. B. bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell. 1993 Aug 27;74(4):597–608. doi: 10.1016/0092-8674(93)90508-n. [DOI] [PubMed] [Google Scholar]
  10. Boyd J. M., Gallo G. J., Elangovan B., Houghton A. B., Malstrom S., Avery B. J., Ebb R. G., Subramanian T., Chittenden T., Lutz R. J. Bik, a novel death-inducing protein shares a distinct sequence motif with Bcl-2 family proteins and interacts with viral and cellular survival-promoting proteins. Oncogene. 1995 Nov 2;11(9):1921–1928. [PubMed] [Google Scholar]
  11. Budman D. R., Calabro A., Wang L. G., Liu X. M., Stiel L., Adams L. M., Kreis W. Synergism of cytotoxic effects of vinorelbine and paclitaxel in vitro. Cancer Invest. 2000;18(8):695–701. doi: 10.3109/07357900009012201. [DOI] [PubMed] [Google Scholar]
  12. Budman D. R. Vinorelbine (Navelbine): a third-generation vinca alkaloid. Cancer Invest. 1997;15(5):475–490. doi: 10.3109/07357909709047587. [DOI] [PubMed] [Google Scholar]
  13. Donaldson K. L., Goolsby G. L., Kiener P. A., Wahl A. F. Activation of p34cdc2 coincident with taxol-induced apoptosis. Cell Growth Differ. 1994 Oct;5(10):1041–1050. [PubMed] [Google Scholar]
  14. Germain M., Affar E. B., D'Amours D., Dixit V. M., Salvesen G. S., Poirier G. G. Cleavage of automodified poly(ADP-ribose) polymerase during apoptosis. Evidence for involvement of caspase-7. J Biol Chem. 1999 Oct 1;274(40):28379–28384. doi: 10.1074/jbc.274.40.28379. [DOI] [PubMed] [Google Scholar]
  15. Haldar S., Basu A., Croce C. M. Bcl2 is the guardian of microtubule integrity. Cancer Res. 1997 Jan 15;57(2):229–233. [PubMed] [Google Scholar]
  16. 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]
  17. Haldar S., Jena N., Croce C. M. Inactivation of Bcl-2 by phosphorylation. Proc Natl Acad Sci U S A. 1995 May 9;92(10):4507–4511. doi: 10.1073/pnas.92.10.4507. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Henderson S., Huen D., Rowe M., Dawson C., Johnson G., Rickinson A. Epstein-Barr virus-coded BHRF1 protein, a viral homologue of Bcl-2, protects human B cells from programmed cell death. Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8479–8483. doi: 10.1073/pnas.90.18.8479. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hengartner M. O., Horvitz H. R. C. elegans cell survival gene ced-9 encodes a functional homolog of the mammalian proto-oncogene bcl-2. Cell. 1994 Feb 25;76(4):665–676. doi: 10.1016/0092-8674(94)90506-1. [DOI] [PubMed] [Google Scholar]
  20. Hirokawa N. Microtubule organization and dynamics dependent on microtubule-associated proteins. Curr Opin Cell Biol. 1994 Feb;6(1):74–81. doi: 10.1016/0955-0674(94)90119-8. [DOI] [PubMed] [Google Scholar]
  21. Jänicke R. U., Sprengart M. L., Wati M. R., Porter A. G. Caspase-3 is required for DNA fragmentation and morphological changes associated with apoptosis. J Biol Chem. 1998 Apr 17;273(16):9357–9360. doi: 10.1074/jbc.273.16.9357. [DOI] [PubMed] [Google Scholar]
  22. Kaufmann S. H., Desnoyers S., Ottaviano Y., Davidson N. E., Poirier G. G. Specific proteolytic cleavage of poly(ADP-ribose) polymerase: an early marker of chemotherapy-induced apoptosis. Cancer Res. 1993 Sep 1;53(17):3976–3985. [PubMed] [Google Scholar]
  23. Lazebnik Y. A., Kaufmann S. H., Desnoyers S., Poirier G. G., Earnshaw W. C. Cleavage of poly(ADP-ribose) polymerase by a proteinase with properties like ICE. Nature. 1994 Sep 22;371(6495):346–347. doi: 10.1038/371346a0. [DOI] [PubMed] [Google Scholar]
  24. Lieu C. H., Liu C. C., Yu T. H., Chen K. D., Chang Y. N., Lai Y. K. Role of mitogen-activated protein kinase in taxol-induced apoptosis in human leukemic U937 cells. Cell Growth Differ. 1998 Sep;9(9):767–776. [PubMed] [Google Scholar]
  25. Lindahl T., Satoh M. S., Poirier G. G., Klungland A. Post-translational modification of poly(ADP-ribose) polymerase induced by DNA strand breaks. Trends Biochem Sci. 1995 Oct;20(10):405–411. doi: 10.1016/s0968-0004(00)89089-1. [DOI] [PubMed] [Google Scholar]
  26. Nishio K., Arioka H., Ishida T., Fukumoto H., Kurokawa H., Sata M., Ohata M., Saijo N. Enhanced interaction between tubulin and microtubule-associated protein 2 via inhibition of MAP kinase and CDC2 kinase by paclitaxel. Int J Cancer. 1995 Nov 27;63(5):688–693. doi: 10.1002/ijc.2910630514. [DOI] [PubMed] [Google Scholar]
  27. Oltvai Z. N., Korsmeyer S. J. Checkpoints of dueling dimers foil death wishes. Cell. 1994 Oct 21;79(2):189–192. doi: 10.1016/0092-8674(94)90188-0. [DOI] [PubMed] [Google Scholar]
  28. Panvichian R., Orth K., Pilat M. J., Day M. L., Day K. C., Yee C., Kamradt J. M., Pienta K. J. Signaling network of paclitaxel-induced apoptosis in the LNCaP prostate cancer cell line. Urology. 1999 Oct;54(4):746–752. doi: 10.1016/s0090-4295(99)00224-1. [DOI] [PubMed] [Google Scholar]
  29. Patton S. E., Martin M. L., Nelsen L. L., Fang X., Mills G. B., Bast R. C., Jr, Ostrowski M. C. Activation of the ras-mitogen-activated protein kinase pathway and phosphorylation of ets-2 at position threonine 72 in human ovarian cancer cell lines. Cancer Res. 1998 May 15;58(10):2253–2259. [PubMed] [Google Scholar]
  30. Raffaelli N., Yamauchi P. S., Purich D. L. Microtubule-associated protein autophosphorylation alters in vitro microtubule dynamic instability. FEBS Lett. 1992 Jan 13;296(1):21–24. doi: 10.1016/0014-5793(92)80394-v. [DOI] [PubMed] [Google Scholar]
  31. Reed J. C. Bcl-2 and the regulation of programmed cell death. J Cell Biol. 1994 Jan;124(1-2):1–6. doi: 10.1083/jcb.124.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Rossini G. P., Sgarbi N., Malaguti C. The toxic responses induced by okadaic acid involve processing of multiple caspase isoforms. Toxicon. 2001 Jun;39(6):763–770. doi: 10.1016/s0041-0101(00)00202-6. [DOI] [PubMed] [Google Scholar]
  33. Sims J. L., Berger S. J., Berger N. A. Poly(ADP-ribose) Polymerase inhibitors preserve nicotinamide adenine dinucleotide and adenosine 5'-triphosphate pools in DNA-damaged cells: mechanism of stimulation of unscheduled DNA synthesis. Biochemistry. 1983 Oct 25;22(22):5188–5194. doi: 10.1021/bi00291a019. [DOI] [PubMed] [Google Scholar]
  34. Sommercorn J., Mulligan J. A., Lozeman F. J., Krebs E. G. Activation of casein kinase II in response to insulin and to epidermal growth factor. Proc Natl Acad Sci U S A. 1987 Dec;84(24):8834–8838. doi: 10.1073/pnas.84.24.8834. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Srivastava R. K., Srivastava A. R., Korsmeyer S. J., Nesterova M., Cho-Chung Y. S., Longo D. L. Involvement of microtubules in the regulation of Bcl2 phosphorylation and apoptosis through cyclic AMP-dependent protein kinase. Mol Cell Biol. 1998 Jun;18(6):3509–3517. doi: 10.1128/mcb.18.6.3509. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Tewari M., Quan L. T., O'Rourke K., Desnoyers S., Zeng Z., Beidler D. R., Poirier G. G., Salvesen G. S., Dixit V. M. Yama/CPP32 beta, a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate poly(ADP-ribose) polymerase. Cell. 1995 Jun 2;81(5):801–809. doi: 10.1016/0092-8674(95)90541-3. [DOI] [PubMed] [Google Scholar]
  37. Wang L. G., Liu X. M., Budman D. R., Kreis W. Synergistic effect of estramustine and [3'-keto-Bmtl]-[Val2]-cyclosporine (PSC 833) on the inhibition of androgen receptor phosphorylation in LNCaP cells. Biochem Pharmacol. 1999 Oct 1;58(7):1115–1121. doi: 10.1016/s0006-2952(99)00210-5. [DOI] [PubMed] [Google Scholar]
  38. Wang L. G., Liu X. M., Kreis W., Budman D. R. The effect of antimicrotubule agents on signal transduction pathways of apoptosis: a review. Cancer Chemother Pharmacol. 1999;44(5):355–361. doi: 10.1007/s002800050989. [DOI] [PubMed] [Google Scholar]
  39. Wang L. G., Liu X. M., Li Z. R., Denstman S., Bloch A. Differential binding of nuclear c-ets-1 protein to an intron I fragment of the c-myb gene in growth versus differentiation. Cell Growth Differ. 1994 Nov;5(11):1243–1251. [PubMed] [Google Scholar]
  40. Wang L. G., Liu X. M., Wikiel H., Bloch A. Activation of casein kinase II in ML-1 human myeloblastic leukemia cells requires IGF-1 and transferrin. J Leukoc Biol. 1995 Feb;57(2):332–334. doi: 10.1002/jlb.57.2.332. [DOI] [PubMed] [Google Scholar]
  41. Wang T. H., Wang H. S., Ichijo H., Giannakakou P., Foster J. S., Fojo T., Wimalasena J. Microtubule-interfering agents activate c-Jun N-terminal kinase/stress-activated protein kinase through both Ras and apoptosis signal-regulating kinase pathways. J Biol Chem. 1998 Feb 27;273(9):4928–4936. doi: 10.1074/jbc.273.9.4928. [DOI] [PubMed] [Google Scholar]
  42. Wang X., Martindale J. L., Liu Y., Holbrook N. J. The cellular response to oxidative stress: influences of mitogen-activated protein kinase signalling pathways on cell survival. Biochem J. 1998 Jul 15;333(Pt 2):291–300. doi: 10.1042/bj3330291. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. White E. Life, death, and the pursuit of apoptosis. Genes Dev. 1996 Jan 1;10(1):1–15. doi: 10.1101/gad.10.1.1. [DOI] [PubMed] [Google Scholar]
  44. 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]

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

RESOURCES