Vinblastine suppresses dynamics of individual microtubules in living interphase cells.

Dhamodharan, Rama; Jordan, Mary Ann; Thrower, Douglas; Wilson, Leslie; Wadsworth, Patricia

doi:10.1091/mbc.6.9.1215

Cited by 162 publications

(157 citation statements)

References 56 publications

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“…These cells were also partially cross-resistant to paclitaxel. In this study, we observed an increase in P. (Jordan et al, 1992;Derry et al, 1995;Dhamodharan et al, 1995). Using purified 0-tubulin isotypes, Panda et al (1994) have shown that microtubule dynamics are regulated by the tubulin isotype composition.…”

Section: Discussionsupporting

confidence: 57%

Altered β-tubulin isotype expression in paclitaxel-resistant human prostate carcinoma cells

Ranganathan

Benetatos²,

Colarusso³

et al. 1998

Br J Cancer

196

133

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Summary To investigate the role of ,B-tubulin isotype composition in resistance to paclitaxel, an anti-microtubule agent, human prostate carcinoma (DU-145) cells were intermittently exposed to increasing concentrations of paclitaxel. Cells that were selected and maintained at 10 nm paclitaxel (Pac-1 0) were fivefold resistant to the drug. Pac-1 0 cells accumulated radiolabelled paclitaxel to the same extent as DU-1 45 cells and were negative for MDR-1. Analysis of Pac-10 and DU-145 cells by flow cytometry showed similar cell cycle patterns. Immunofluorescent staining revealed an overall increase of a-and 1-tubulin levels in Pac-10 cells compared with DU-145 cells. Examination of 3-tubulin isotype composition revealed a significant increase in pill isotype in the resistant cells, both by immunofluorescence and by western blot analysis. Reverse transcription-polymerase chain reaction (RT-PCR) analysis of the isotypes confirmed the increase observed for the ,,, by exhibiting ninefold higher ,,, mRNA levels and also showed fivefold increase of the Plv. transcript. In addition, analysis of paclitaxel-resistant cells that were selected at increasing levels of the drug (Pac 2, 4, 6, 8 and 10) exhibited a positive correlation between increasing P,,, levels and increasing resistance to paclitaxel. Increased expression of specific ,B-tubulin isotypes and subsequent incorporation into microtubules may alter cellular microtubule dynamics, providing a defence against the anti-microtubule effects of paclitaxel and other tubulin-binding drugs.Paclitaxel has gained considerable attention in cancer therapy in recent years and is successfully used in treating a variety of tumours, including those of the breast, ovary and lung. In treatment of prostate cancer, paclitaxel is inactive when used as a single agent (Roth et al, 1993). However, in combination with estramustine, another anti-microtubule agent, paclitaxel has significant activity against hormone refractory prostate cancer (Hudes et al, 1995).Despite its preclinical and clinical success, the exact mechanism of action of paclitaxel is not known. At low concentrations, paclitaxel blocks mitosis by kinetic stabilization of spindle microtubules (Jordan et al, 1993). Paclitaxel differs from the other anti-microtubule agents such as vinblastine and colchicine by causing microtubule polymerization instead of depolymerization.The c4p-tubulin heterodimer is the major component of microtubules. Most of the anti-microtubule agents, including paclitaxel, vinblastine, colchicine and estramustine bind to 3-tubulin. Paclitaxel binding sites on 3-tubulin were identified at the N-terminal 31 amino acids and at residues 217-231 of the protein . These two binding sites are part of the colchicine binding site and are highly conserved among species.Both a-and ,-tubulins are encoded by multigene families and exist as several isotypes in cells. 3-Tubulin exists as six isotypes that are evolutionarily conserved across species and differ from each other predominantly at the carboxy terminus. Sever...

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Section: Discussionsupporting

confidence: 57%

Altered β-tubulin isotype expression in paclitaxel-resistant human prostate carcinoma cells

Ranganathan

Benetatos²,

Colarusso³

et al. 1998

Br J Cancer

196

133

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“…Because antimicrotubule agents are widely used in cancer therapy, tubulin isotype composition of tumour cells may be an important factor in the success of therapy. Estramustine, vinblastine and paclitaxel have been shown to suppress microtubule dynamics at very low drug concentrations (Jordan et al, 1993(Jordan et al, , 1996Dhamodharan et al, 1995;Panda et al, 1997). Work by Lu and Luduena (1993) demonstrated that microtubules lacking the β III isotype polymerized at a faster rate in the presence of paclitaxel than the microtubules from unfractioned tubulin.…”

Section: Discussionmentioning

confidence: 99%

Modulation of endogenous β -tubulin isotype expression as a result of human βIIIcDNA transfection into prostate carcinoma cells

et al. 2001

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In the past several years many laboratories have studied the significance of α and β tubulin proteins in antimicrotubule drug resistance. These studies have extended to several antimicrotubule agents in various carcinoma cell lines. Early studies showed mutations and alterations in the steady state soluble and polymerized α and β tubulin fractions in drug resistant cell lines Cabral et al, 1986;Minotti et al, 1991). Although the existence of different α and β tubulin isotypes and their tissue specific expression was reported in the past, only recently demonstrated were the effects of individual β tubulin isotypes on overall microtubule functions including assembly, dynamics, drug sensitivity and drug binding. Banerjee et al (1990) have shown that β III isotype depleted tubulin assembles into microtubules at a faster rate than unfractioned tubulin. These microtubules are also more sensitive to paclitaxel-induced assembly compared to unfractioned tubulin (Lu and Luduena, 1993). Subsequent studies revealed alterations in the expression of specific β tubulin isotypes as result of antimicrotubule drug resistance (Haber et al, 1995;Ranganathan et al, 1996;1998a;1998b;Kavallaris et al, 1997;Kavallaris et al, 1999). In addition, combination studies have shown that cyclosporin A enhances paclitaxel efficacy in lung carcinoma cell lines by modulating β tubulin isotype composition (Ross and Antoniono, 1999). Recently, Kavallaris et al, (1999) have shown that antisense oligonucleotides to β III isotype sensitized the drug resistant cells to paclitaxel. In addition, mutations in β I isotype were reported in paclitaxel resistant human ovarian carcinoma cells (Giannakakou et al, 1997), breast carcinoma cells (Wiesen and Horwitz, 2000) and non-small-cell lung cancer patients (Monzo et al, 1999) with tumours that were unresponsive to paclitaxel therapy.Antimicrotubule drug resistance associated changes in tubulin isotypes prompted several investigators to determine the contribution of individual isotypes by transfecting cells and examining their antimicrotubule drug response. Wu et al (1998) have shown that transfection of β IVa isotype into human leukemic cell line failed to confer resistance to paclitaxel. Blade et al (1999) have over-expressed rodent β I , β II or β IVb isotypes in CHO cells and shown that these isotypes do not confer resistance to paclitaxel. Our previous work demonstrated increases in β III and β IVa isotypes in human prostate carcinoma cells that were made resistant to estramustine or paclitaxel (Ranganathan et al, 1996(Ranganathan et al, , 1998a. In addition, acute exposures to these agents resulted in elevations of β III levels. To further understand the function of β III isotype in antimicrotubule drug response, parental DU145 human carcinoma cells were transfected with the human β III cDNA. The results presented herein indicate that regulation of tubulin in cells is complex and that attempts to increase levels of a single isotype may lead to compensatory changes in the expression of other isotypes. Sum...

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“…This enhanced stability may also explain the large increase in average microtubule length. Based upon in vitro experiments, it has been postulated that animal MAPs stimulate the growth of microtubules not by increasing the rate of polymerization but by decreasing disassembly (7,26,27). The dilution experiments showed that disassembly of microtubules was markedly slower in the presence of MAP60, which may therefore stimulate microtubule growth in the same way neuronal MAPs do, that is, by decreasing disassembly.…”

Section: Discussionmentioning

confidence: 99%

A 60-kDa plant microtubule-associated protein promotes the growth and stabilization of neurotubules in vitro

Rutten

Chan

Lloyd

1997

Proc. Natl. Acad. Sci. U.S.A.

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The search for microtubule-associated proteins (MAPs) in plants is relatively recent. In particular, the ''classical MAPs,'' which stimulate the polymerization and stabilization of microtubules, have only been examined in heterogeneous fractions. As a first step in dissecting the role of individual MAPs, we have chromatographically purified a single 60-kDa protein from a carrot MAP fraction and analyzed its effects on tubulin assembly. MAP60 promoted the formation of long, morphologically regular brain microtubules in vitro, an effect inhibited by preincubation of the MAP with affinity-purified antibodies against this protein. MAP60 also increased the stability of microtubules to dilution and significantly enhanced cold stability to the normally coldsensitive neurotubules. These in vitro properties are consistent with a role for MAP60 in regulating the turnover͞assembly of dynamic plant microtubules in vivo.

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Vinblastine suppresses dynamics of individual microtubules in living interphase cells.

Cited by 162 publications

References 56 publications

Altered β-tubulin isotype expression in paclitaxel-resistant human prostate carcinoma cells

Altered β-tubulin isotype expression in paclitaxel-resistant human prostate carcinoma cells

Modulation of endogenous β -tubulin isotype expression as a result of human βIIIcDNA transfection into prostate carcinoma cells

A 60-kDa plant microtubule-associated protein promotes the growth and stabilization of neurotubules in vitro

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