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. © 2001 Cancer Research Campaign http://www.bjcancer.com
Similar content being viewed by others
Article PDF
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Alessi DR, Cuenda A, Cohen P, Dudley DT and Saltil AR (1995) PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and vivo. J Biol Chem 270: 27489–27494
Attalla H, Westberg JA, Andersson LC, Adlercreutz H and Makela TP (1998) 2-Methoxyestradiol-induced phosphorylation of bcl-2: uncoupling from JNK/SAPK activation. Biochem Biophys Res Commun 247: 616–619
Avruch J, Zhang X and Kyriakis JM (1994) Raf meets Ras: completing the framework of a signal transduction pathway. Trends Biochem Sci 19: 279–283
Basu A and Haldar S (1998) Microtubule-damaging drugs triggered bcl-2 phosphorylation-requirement of phosphorylation on both serine-70 and serine-87 residues of bcl-2 protein. Int J Oncol 13: 659–664
Blagosklonny MV, Schulte TW, Nguyen P, Mimnaugh EG, Trepel J and Neckers LM (1995) Taxol induction of p21WAF1 and p53 requires c-raf-1. Cancer Res 55: 4623–4626
Blagosklonny MV, Schulte T, Nguyen P, Trepel J and Neckers LM (1996) 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 56: 1851–1854
Blagosklonny MV, Giannakakou P, el-Deiry WS, Kingston DG, Higgs PI, Necker LM and Fojo T (1997) Raf-1/bcl-2 phosphorylation: a step from microtubule damage to cell death. Cancer Res 57: 130–135
Blagosklonny MV, Bishop PC, Robey R, Fojo T and Bates SE (2000) Loss of cell cycle control allows selective microtubule-active drug-induced Bcl-2 phosphorylation and cytotoxicity in autonomous cancer cells. Cancer Res 60: 3425–3428
Boise LH, Gonzalez-Garcia M, Postema CE, Ding L, Lindsten T, Turka LA, Mao X, Nunez G and Thompson CB (1993) Bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell 74: 597–608
Boyd JM, Gallo GJ, Elangovan B, Houghton AB, Malstrom S, Avery BJ, Ebb RG, Subramanian T, Chittenden T and Lutz RT (1995) 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 11: 1921–1928
Budman DR (1997) Vinorelbine (Navelbine): a third-generation vinca alkaloid. Cancer Invest 15: 475–490
Budman DR, Calabro A, Wang LG, Liu XM, Stiel L, Adams LM and Kreis W (2000) Synergism of cytotoxic effects of vinorelbine and paclitaxel in vitro. Cancer Invest 18: 695–701
Donaldson KL, Goolsby GL, Kiener PA and Wahl AF (1994) Activation of p34cdc2 coincident with taxol-induced apoptosis. Cell Growth Differ 5: 1041–1050
Germain M, Affar EB, D'Amours D, Dixit VM, Salvesen GS and Poirier GG (1999) Cleavage of automodified poly(ADP-ribose) polymerase during apoptosis. Evidence for involvement of caspase-7. J Biol Chem 274: 28379–28384
Haldar S, Jena N and Croce CM (1995) Inactivation of bcl-2 by phosphorylation. Proc Natl Acad Sci USA 92: 4507–4511
Haldar S, Chintapalli J and Croce CM (1996) Taxol induces bcl-2 phosphorylation and death of prostate cancer cells. Cancer Res 56: 1253–1255
Haldar S, Basu A and Croce CM (1997) Bcl-2 is the guardian of microtubule integrity. Cancer Res 57: 229–233
Henderson S, Huen D, Rowe M, Dawson C, Johnson G and Rickinoson A (1993) Epstein-Barr virus-coded BHRF1 protein, a viral homologue of Bcl-2, protects human B cells from programmed cell death. Proc Natl Acad Sci USA 90: 8479–8483
Hengartner MO and Horvitz HR (1994) Celegans cell survival gene ced-9 encodes a functional homolog of the mammalian proto-oncogene bcl-2. Cell 76: 665–676
Hirokawa N (1994) Microtubule organization and dynamics dependent on microtubule-associated proteins. Curr Opin Cell Biol 6: 74–81
Janicke RU, Sprengart ML, Wati MR and Porter AG (1998) Caspase-3 is required for DNA fragmentation and morphological changes associated with apoptosis. J Biol Chem 273: 9357–9360
Kaufmann SH, Desnoyers S, Ottaviano Y, Davidson NE and Poirier GG (1993) Specific proteolytic cleavage of poly(ADP-ribose) polymerase: an early marker of chemotherapy-induced apoptosis. Cancer Res 53: 3976–3985
Lazebnik YA, Kaufmann SH, Desnoyers S, Poirier GG and Earnshaw WC (1994) Cleavage of poly(ADP-ribose) polymerase by a proteinase with properties like ICE. Nature 371: 346–347
Lieu CH, Liu CC, Yu TH, Chen KD, Chang YN and Lai YK (1998) Role of mitogen-activated protein kinase in taxol-induced apoptosis in human leukemic U937 cells. Cell Growth Differ 9: 767–776
Lindahl T, Satoch MS, Poirier GG and Klungland A (1995) Post-translational modification of poly(ADP-ribose) polymerase induced by DNA strand breaks. Trends Biochem Sci 20: 405–411
Nishio K, Arioka H, Ishida T, Fukumoto H, Kurokawa H, Sata M, Ohata M and Saijo N (1995) Enhanced interaction between tubulin and microtubule-associated protein 2 via inhibition of MAP kinase and CDC2 kinase by paclitaxel. Int J Cancer 63: 688–693
Oltvai ZN and Korsmeyer SJ (1994) Checkpoints of dueling dimers foil death wishes. Cell 79: 189–192
Panvichian R, Orth K, Pilat MJ, Day ML, Day KC, Yee C, Kamradt JM and Pienta KJ (1999) Signaling network of paclitaxel-induced apoptosis in the LNCaP prostate cancer cell line. Urology 54: 746–752
Patton SE, Martin ML, Nelsen LL, Fang X, Mills GB, Bast RC Jr and Ostrowski MC (1998) 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 58: 2253–2259
Raffaelli N, Yamauchi PS and Purichi DL (1992) Microtubule-associated protein auto-phosphorylation alters in vitro microtubule dynamic instability. FEBS Lett 296: 21–24
Reed JC (1994) Bcl-2 and the regulation of programmed cell death. J Cell Biol 124: 1–6
Rossini GP, Sgarbi N and Malaguti C (2001) The toxic responses induced by okadaic acid involve processing of multiple caspase isoforms. Toxicon 39: 763–770
Sims JL, Berger SJ and Berger NA (1983) 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 22: 5188–5194
Sommercorn J, Mulligan JA, Lozeman FJ and Krebs EG (1987) Activation of casein kinase II in response to insulin and to epidermal growth factor. Proc Natl Acad Sci USA 84: 8834–8838
Srivastava RK, Srivastava AR, Korsmeyer SJ, Nesterova M, Cho-Chung YS and Longo DL (1998) Involvement of microtubules in the regulation of bcl-2 phosphorylation and apoptosis through cyclic AMP-dependent protein kinase. Mol Cell Biol 18: 3509–3517
Tewari M, Quan LT, O'Rourke K, Desnoyers S, Zeng Z, Beidler DR, Poirier GG, Salvesen GS and Dixit VM (1995) Yama/CPP32b, a mammalian homolog of CED-3, is a crm-A-inhibitable protease that cleaves the death substrate poly(ADP-ribose) polymerase. Cell 81: 801–809
Wang LG, Liu XM, Li ZR, Denstman S and Bloch A (1994) 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 5: 1243–1251
Wang LG, Liu XM, Wikiel H and Bloch A (1995) Activation of casein kinase II in ML-1 human myeloblastic leukemia cells requires IGF-1 and transferrin. J Leukocyte Biol 57: 332–334
Wang LG, Liu XM, Kreis W and Budman DR (1996) Involvement of prostate-specific antigen in the stimulation of LNCaP cell growth. Oncol Report 3: 911–917
Wang TH, Wang HS, Ichijo H, Giannakakou P, Foster JS, Fojo T and Wimalasena J (1998a) 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 273: 4928–4936
Wang X, Martindale JL, Liu Y and Holbrook NJ (1998b) The cellular response to oxidative stress: influences of mitogen-activated protein kinase signaling pathways on cell survival. Biochem J 333: 291–300
Wang LG, Liu XM, Kreis W and Budman DR (1999a) The effect of antimicrotubule agents on signal transduction pathways of apoptosis: A review. Cancer Chemother Pharmacol 44: 355–361
Wang LG, Liu XM, Kreis W and Budman DR (1999b) Synergistic effect of Estramustine and PSC 833 on the inhibition of androgen receptor phosphorylation. Biochem Pharmacol 58: 1115–1121
White E (1996) Life, death and the pursuit of apoptosis. Genes Dev 10: 1–15
Yamamoto K, Ichijo H and Korsmeyer SJ (1999) Bcl-2 is phosphorylated and inactivated by an ASK1/Jun N-terminal protein kinase pathway normally activated at G2/M. Mol Cell Biol 19: 8469–8478
Author information
Authors and Affiliations
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Liu, X., Wang, L., Kreis, W. et al. Differential effect of vinorelbine versus paclitaxel on ERK2 kinase activity during apoptosis in MCF-7 cells. Br J Cancer 85, 1403–1411 (2001). https://doi.org/10.1054/bjoc.2001.2107
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1054/bjoc.2001.2107
Keywords
This article is cited by
-
The microtubule depolymerizing agent naphthazarin induces both apoptosis and autophagy in A549 lung cancer cells
Apoptosis (2011)
-
Structure-activity relationships between the Aconitum C20-diterpenoid alkaloid derivatives and the growth suppressive activities of Non-Hodgkin’s lymphoma Raji cells and human hematopoietic stem/progenitor cells
Investigational New Drugs (2011)
-
The role of apoptotic cell death in the radiosensitising effect of gemcitabine
British Journal of Cancer (2009)
-
The PI3K inhibitor LY294002 blocks drug export from resistant colon carcinoma cells overexpressing MRP1
Oncogene (2006)
-
Analysis of mechanisms contributing to AraC-mediated chemoresistance and re-establishment of drug sensitivity by the novel heterodinucleoside phosphate 5-FdUrd-araC
Apoptosis (2006)