Induction of senescence-like phenotype and loss of paclitaxel sensitivity after wild-type p53 gene transfection of p53-null human non-small cell lung cancer h358 cells

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Abstract

The p53 gene plays an important role in the regulation of cell-cycle progression and apoptosis. Recent studies have implicated p53 in determining cell fate, and shown that p53 status is associated with cellular sensitivity to anticancer agents. However, the role of p53 in paclitaxel-induced cytotoxicty remains unclear. Here we show that the induction of exogenous wild-type (wt) p53 genes in p53-null human NSCLC H358 cells via transient gene transfection with cationic liposome-wt p53 complexes resulted in a typical senescence-like phenotype. In short, cell growth was reduced, homeostasis occurred cell morphology became enlarged and flat, the cell cycle was arrested at GI phase, cyclin B1 and cdc2 expression was down-regulated, and DNA synthesis was suppressed. The sensitivity of wt p53-transfected cells (H358/p53) to paclitaxel was ~ 3-fold lower than that of H358 cells. Paclitaxel treatment gradually and significantly blocked cell-cycle progression at G2/M phase and increased the accumulation of cyclin BI and cdc2 in H358 cells. In contrast, the same treatment slightly arrested the cell cycle at G2/M phase and slightly elevated cyclin BI expression in H358/p53 cells. The rate of uptake and efflux of paclitaxel was not significantly different between H358 and H358/p53 cells, indicating that the reduction in cellular sensitivity caused by p53 transfection was not due to alterasion in intracellular drug concentration. Together, our findings suggest that the induction of exogenous wt p53 gene expression in cells lacking p53 function can trigger the senescence program and that loss of sensitivity to paclitaxel by p53-transfected cells may be associated, at least in part, with the induction of a senescence-like phenotype.

Original languageEnglish (US)
Pages (from-to)693-702
Number of pages10
JournalAnticancer Research
Volume20
Issue number2 A
Publication statusPublished - May 16 2000
Externally publishedYes

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Keywords

  • Cell lung cancer cells
  • Paclitaxel sensitivity
  • Senescence
  • p53 gene transfection

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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