Paclitaxel-resistant Human Ovarian Cancer Cells Have Mutant β-Tubulins That Exhibit Impaired Paclitaxel-driven Polymerization

Giannakakou, Paraskevi; Sackett, Dan L.; Kang, Yoon‐Koo; Zhan, Zhirong; Buters, Jeroen; Fojo, Tito; Poruchynsky, Marianne S.

doi:10.1074/jbc.272.27.17118

Cited by 643 publications

(607 citation statements)

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“…For example, β-tubulin mutation and alterations have been shown to be associated with paclitaxel resistance (Ranganathan et al, 1988(Ranganathan et al, , 1996(Ranganathan et al, , 1998Haber et al, 1995;Giannakakou et al, 1997;Kavallaris et al, 1997Kavallaris et al, , 1999. We have shown that α-tubulin also contributes paclitaxel resistance (Han et al, 1999).…”

Section: Bmentioning

confidence: 50%

“…P-glycoprotein (P-gp), an energy-dependent drug efflux pump shown to confer multidrug resistance (MDR) Pastan, 1988, 1993;Lehnert, 1996;Germann, 1996) 2. alterations in β-tubulin isotypes (Haber et al, 1995;Ranganathan et al, 1988Kavallaris et al, 1997 3. mutations in tubulins (Cabral et al, 1981;Schibler and Cabral, 1986;Giannakakou et al, 1997) 4. up-regulation of caveolin-1 (Yang et al, 1998.…”

mentioning

confidence: 99%

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Modulation of paclitaxel resistance by annexin IV in human cancer cell lines

Han¹,

Tahir²,

Cherian³

et al. 2000

Br J Cancer

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Efficacy of paclitaxel in cancer patients has been hampered by the ability of cells to develop paclitaxel resistance (Rowinsky et al, 1992;Rowinsky and Donehower, 1995). Therefore if we understand the mechanism of paclitaxel resistance we will be more successful in the treatment of human cancer. It has been shown that several factors contribute to paclitaxel resistance in vitro:1. P-glycoprotein (P-gp), an energy-dependent drug efflux pump shown to confer multidrug resistance (MDR) Pastan, 1988, 1993;Lehnert, 1996;Germann, 1996) 2. alterations in β-tubulin isotypes (Haber et al, 1995;Ranganathan et al, 1988Kavallaris et al, 1997 3. mutations in tubulins (Cabral et al, 1981;Schibler and Cabral, 1986;Giannakakou et al, 1997) 4. up-regulation of caveolin-1 (Yang et al, 1998.Paclitaxel also activates molecules that are involved in signal transduction pathways such as c-jun N-terminal kinase (Blagosklonny et al, 1995;Wolfson et al, 1997;Wang et al, 1998).Annexins are a family of calcium-dependent phospholipid binding proteins. There are at least 13 annexin family members with a similar structure, characterized by the presence of four or eight repeats of a 70 amino acid motif and a variable N-terminal end (Smith and Moss, 1994;Dubois et al, 1996;Benz-and Hofmann, 1997). Although the roles of the annexins are not well understood, they have been involved in various biological processes including inhibition of phospholipase A2, anticoagulation, endocytosis, exocytosis, inhibition of calcium channels and protein kinase C activity (Smith and Moss, 1994). It was also previously shown that annexin II was elevated in doxorubicin-resistant small-cell lung cancer cell line (Cole et al, 1992). During the course of our antimitotic research, we found that annexin IV was overexpressed in A204197-resistant human colon cancer HCT-15 cells as determined by two-dimensional protein mapping as well as mass spectroscopic analysis. Therefore, we tested whether annexin IV or annexin II was also overexpressed in a paclitaxel-resistant cell line, H460/T800. To our surprise annexin IV, but not annexin II, was overexpressed in the paclitaxel-resistant H460 lung cancer cell line. To further confirm the role of annexin IV in drug resistance, annexin IV cDNA was transfected into 293T cells. Annexin IV transfectants were more resistant to paclitaxel as compared to the vector controls. Thus our study indicates that annexin IV plays a role in regulating paclitaxel resistance. MATERIALS AND METHODS Cell cultureLung cancer cell line NCI-H460 (hereafter referred to as H460) and colon cancer cell line HCT15 were obtained from the American Tissue Culture Collection (ATCC) H460 and HCT15 cells were grown and maintained in RPMI medium plus 10% fetal bovine serum (FBS) or 20% FBS respectively. Paclitaxel-resistant cell lines were derived from the H460 parental cell line. H460 cells were initially selected with IC 50 concentration of paclitaxel and thereafter paclitaxel concentration was doubled every 2-3 weeks until 800 nM paclitaxel resistance was obtain...

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Section: Bmentioning

confidence: 50%

mentioning

confidence: 99%

Modulation of paclitaxel resistance by annexin IV in human cancer cell lines

Han¹,

Tahir²,

Cherian³

et al. 2000

Br J Cancer

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“…However, we cannot exclude that alterations in microtubular network observed in MDD2 cells were also because of genetic drift over time; chromosomal aberrations were present in the mut-p53 as demonstrated by the tetraploidy (Galmarini et al, 2001) and centrosome amplification observed in these cells. Different studies have demonstrated that the loss of p53 function leads to genetic instability allowing cells to accumulate mutations in many genes, including b-tubulin mutations (Giannakakou et al, 1997(Giannakakou et al, , 2000a. Silencing of p53 may thus predispose MDD2 cells to accumulate b-tubulin alterations that would alter microtubule composition and dynamics conferring resistance to microtuble-targeted drugs.…”

Section: Discussionmentioning

confidence: 99%

Drug resistance associated with loss of p53 involves extensive alterations in microtubule composition and dynamics

et al. 2003

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In the present study, we compared the dynamics and composition of microtubules in cell lines derived from the human breast adenocarcinoma MCF-7 containing either the wild-type p53 (wt-p53; MN1) or a dominant-negative variant of p53 gene (mut-p53; MDD2). Mut-p53 cells were significantly resistant to the cytotoxicity of the microtubule-targeted drugs (vinca alkaloids and taxanes), as compared with wt-p53 cells. Studies by high-resolution time-lapse fluorescence microscopy in living cells indicated that the dynamics of microtubules of mut-p53 cells were altered in complex ways and were significantly increased as compared with microtubules in wt-p53 cells. The percentage of time microtubules spent in growing and shortening phases increased significantly, their catastrophe frequency increased, and their overall dynamicity increased by 33%. In contrast, their shortening rate and the mean length shortened decreased. Cells containing mut-p53 displayed increased polymerisation of tubulin, increased protein levels of the class IV b-tubulin isotype, STOP and survivin, and reduced protein levels of class II b-tubulin isotype, MAP4 and FHIT. We conclude that p53 protein may contribute to the regulation of microtubule composition and function, and that alterations in p53 function may generate complex microtubule-associated mechanisms of resistance to tubulin-binding agents.

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“…Tumor cells for example can develop resistance to antimitotic inhibitors that target tubulin such as taxanes and vinca alkaloids [42] through mutations in the drug binding site (i.e.  tubulin) [43,44] or by overexpression of the drug efflux pump, P-glycoprotein [45]. The ability to confer drug resistance by introducing mutations in the induced fit binding pocket of Eg5 raises the possibility that such mutations may be encountered in tumors during chemotherapy if Eg5 inhibitors were to enter the clinic.…”

Section: Monastrol and Stlc Have Been Characterized As Eg5 Specific Imentioning

confidence: 99%

Mutations in the human kinesin Eg5 that confer resistance to monastrol and S-trityl-l-cysteine in tumor derived cell lines

Tcherniuk

Lis

Kozielski

et al. 2010

Biochemical Pharmacology

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. Mutations in the human kinesin Eg5 that confer resistance to monastrol and S-Trityl-L-Cysteine in tumor derived cell lines.. Biochemical Pharmacology, Elsevier, 2010, 79 (6) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. confirms the target specificity of monastrol and STLC for Eg5. These data also suggest a possible mechanism by which drug resistance may occur in tumors treated with agents targeting Eg5.

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Paclitaxel-resistant Human Ovarian Cancer Cells Have Mutant β-Tubulins That Exhibit Impaired Paclitaxel-driven Polymerization

Cited by 643 publications

References 44 publications

Modulation of paclitaxel resistance by annexin IV in human cancer cell lines

Modulation of paclitaxel resistance by annexin IV in human cancer cell lines

Drug resistance associated with loss of p53 involves extensive alterations in microtubule composition and dynamics

Mutations in the human kinesin Eg5 that confer resistance to monastrol and S-trityl-l-cysteine in tumor derived cell lines

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