Acquired resistance to peloruside a and laulimalide is associated with downregulation of vimentin in human ovarian carcinoma cells

Arun Kanakkanthara, Pisana Rawson, Peter T. Northcote, John H. Miller

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Purpose: Acquired β-tubulin alterations in human ovarian carcinoma 1A9 cells were previously shown to confer resistance to the microtubule stabilizing agents peloruside A (PLA) and laulimalide (LAU). We examined the proteome of resistant cells to see what other protein changes occurred as a result of the acquired drug resistance. Methods: Two-dimensional differential in-gel electrophoresis was performed to explore differentially expressed proteins in the resistant 1A9-R1 (R1) and 1A9-L4 (L4) cells. The proteins on the gels were identified by MALDI-TOF MS, and altered protein abundance was confirmed by Western blotting and immunocytochemistry. Vimentin expression was restored in vimentin-deficient L4 cells by transfecting a full-length human vimentin cDNA, and sensitivity to PLA and LAU were tested using an MTT cell proliferation assay. Results: Proteomic analysis identified several proteins that were significantly altered in the resistant cells relative to the parental 1A9 cells. Using Western blotting and immunocytochemistry, a decreased vimentin abundance in the L4 cells was validated. Vimentin levels were unchanged in PLA-resistant R1 cells and paclitaxel/epothilone-resistant derivatives of 1A9 cells. Vimentin cDNA transfection into L4 cells partially restored PLA and LAU sensitivity. Conclusions: Downregulation of vimentin contributes to the resistance of 1A9 cells to the microtubule stabilizing agents, PLA and LAU.

Original languageEnglish (US)
Pages (from-to)3022-3032
Number of pages11
JournalPharmaceutical research
Volume29
Issue number11
DOIs
StatePublished - Nov 2012

Keywords

  • cancer resistance
  • laulimalide
  • ovarian carcinoma cells
  • peloruside A
  • vimentin

ASJC Scopus subject areas

  • Biotechnology
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry
  • Pharmacology (medical)

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