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Yeast As a Chassis for Developing Functional Assays to Study Human P53
14:57

Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

Enhanced TRAIL sensitivity by p53 overexpression in human cancer but not normal cell lines

K Kim1, R Takimoto, D T Dicker

  • 1Laboratory of Molecular Oncology and Cell Cycle Regulation, Howard Hughes Medical Institute, Department of Medicine, Philadelphia, PA 19104, USA.

International Journal of Oncology
|February 15, 2001
PubMed

Insights

Adenovirus-p53 (Ad-p53) gene therapy can re-sensitize TRAIL-resistant cancers to TRAIL by upregulating the KILLER/DR5 receptor. This approach shows promise in overcoming resistance mechanisms, enhancing anti-cancer efficacy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Gene Therapy

Background:

  • Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) is a promising anti-cancer therapeutic.
  • TRAIL resistance in cancer is often associated with reduced DR4 expression or elevated FLIP levels.
  • Gene therapy offers a potential strategy to overcome TRAIL resistance.

Purpose of the Study:

  • To investigate the efficacy of adenovirus-p53 (Ad-p53) gene therapy in overcoming TRAIL resistance.
  • To determine if Ad-p53 can modulate TRAIL receptor expression (KILLER/DR5) in cancer cells.
  • To assess the impact of Ad-p53 on TRAIL-induced apoptosis in TRAIL-resistant cancer cell lines.

Main Methods:

  • Utilized an adenovirus-p53 (Ad-p53) vector for gene delivery.
  • Tested Ad-p53 and TRAIL treatment on a panel of 8 cell lines (normal and cancer).
  • Monitored p53 functional status via p21WAF1 induction using immunocytochemistry.
  • Assessed changes in KILLER/DR5 receptor expression and cell viability.

Main Results:

  • Ad-p53 treatment alone did not significantly affect normal cell viability.
  • All cancer cell lines exhibited sensitivity to Ad-p53, with increased KILLER/DR5 receptor expression.
  • TRAIL-resistant cancer cells demonstrated enhanced sensitivity to TRAIL when combined with low Ad-p53 doses.
  • Complete overcoming of TRAIL resistance was not achieved in one cell line, likely due to high FLIP levels.

Conclusions:

  • Ad-p53 gene therapy effectively induces KILLER/DR5 receptor expression in cancer cells.
  • This induction can reverse TRAIL resistance, similar to radiation or chemotherapy.
  • Combining Ad-p53 with TRAIL presents a potential strategy to enhance anti-cancer therapy efficacy.

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