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Altered levels and regulation of stathmin in paclitaxel-resistant ovarian cancer cells

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Abstract

Two paclitaxel(Ptx)-resistant ovarian cancer cell lines, 1A9/Ptx-10 and 1A9/Ptx-22, isolated from the 1A9 cell line (a clone of the A2780 line) by continuous exposure to Ptx and verapamil, have point mutations in their major β-tubulin gene and in one or both alleles of their TP53 gene. These cells were examined for alterations in cell cycle regulators and the tubulin-binding protein stathmin. Unlike parental cells, neither 1A9/Ptx-10 nor 1A9/Ptx-22 expressed detectable levels of p21WAF1/Cip1, a putative transcriptional regulator of stathmin, but did overexpress stathmin and Bcl2. No differences were noted in the expression levels of proliferative cell nuclear antigen or tyrosine-phosphorylated p34Cdc2. Ptx treatment altered little the expression of stathmin in the parental cell line, although it increased p21WAF1/Cip1 levels several-fold. Infection of Ptx-resistant lines with a wild-type TP53-bearing adenovirus (AdWTp53) changed cell cycle distribution and increased the levels of p21WAF1/Cip1, but caused no changes in stathmin levels. Microtubule drug resistance in ovarian carcinoma may be associated with altered p53/21WAF1/Cip1 regulatory pathways for stathmin expression and function.

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Abbreviations

HBSS:

Hank's balanced salts solution

MOI:

multiplicity of infection

MT:

microtubule

PCNA:

proliferative cell nuclear antigen

Ptx:

paclitaxel

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Acknowledgements

We are grateful to Drs Tito Fojo and Paraskevi Giannakakou for providing the 1A9, 1A9/Ptx-10 and 1A9/Ptx-22 cell lines and Dr Shiv Srivastava for the generous gift of AdWTp53 and d1312 control viruses. This work was supported by a grant from the USPHS (CA 78039).

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, 15261, PA, USA

    Raghavan Balachandran & Billy W Day

  2. Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, 15261, PA, USA

    Manda J Welsh

  3. Department of Chemistry, University of Pittsburgh, Pittsburgh, 15261, PA, USA

    Billy W Day

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  1. Raghavan Balachandran
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  2. Manda J Welsh
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  3. Billy W Day
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Correspondence to Billy W Day.

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Balachandran, R., Welsh, M. & Day, B. Altered levels and regulation of stathmin in paclitaxel-resistant ovarian cancer cells. Oncogene 22, 8924–8930 (2003). https://doi.org/10.1038/sj.onc.1207060

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  • DOI: https://doi.org/10.1038/sj.onc.1207060

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