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

Published on: August 4, 2019

Status of p53 phosphorylation and function in sensitive and resistant human cancer models exposed to platinum-based

Kalpana Mujoo1, Masayuki Watanabe, Junichi Nakamura

  • 1Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Box 104, Houston, TX 77030, USA.

Journal of Cancer Research and Clinical Oncology
|September 27, 2003
PubMed
Abstract

Insights

Chemotherapy resistance in cancer can be influenced by p53 gene status. Cisplatin resistance is linked to p53 phosphorylation, but a platinum analog shows differential effects on p53 and downstream genes like p21(WAF1/CIP1).

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Pharmacology

Background:

  • Chemotherapeutic drug resistance is a significant challenge in cancer treatment.
  • Wild-type p53 status in tumors can confer resistance to cisplatin, but not necessarily to all platinum analogs.
  • Understanding p53 phosphorylation and downstream signaling is crucial for overcoming drug resistance.

Purpose of the Study:

  • To investigate DNA damage-induced phosphorylation of p53 in response to cisplatin (CDDP) and a platinum analog (1R,2R-diaminocyclohexane)(trans-diacetato)(dichloro)platinumIV (DACH-Ac-Pt).
  • To examine downstream p53-dependent transactivation events in both sensitive and resistant human cancer cell lines.
  • To elucidate the differential mechanisms of action of CDDP and DACH-Ac-Pt in the context of p53 and drug resistance.

Main Methods:

  • Western-blot analysis was employed to assess p53 phosphorylation and the expression of p53-dependent target genes.
  • Studies were conducted on both cisplatin-sensitive and cisplatin-resistant human cancer cell lines.
  • The effects of wortmannin, a PI3-kinase (PI3-K) inhibitor, were evaluated to understand the role of PI3-K in p53 signaling.

Main Results:

  • Both CDDP and DACH-Ac-Pt induced p53 protein and Ser-15 phosphorylation in a time- and dose-dependent manner, with CDDP showing a more pronounced effect.
  • Ser-392 phosphorylation was observed with CDDP but was weak or absent with DACH-Ac-Pt, yet this did not affect p21(WAF1/CIP1) or Mdm2 induction by the analog.
  • Cisplatin-mediated induction of p21(WAF1/CIP1) was minimal in resistant cells, unlike Mdm2 induction, while DACH-Ac-Pt effectively induced both in resistant cells. PI3-K inhibition affected p53 accumulation, Ser-15 phosphorylation, and p21(WAF1/CIP1) transactivation.

Conclusions:

  • Cisplatin and DACH-Ac-Pt differentially phosphorylate p53 via distinct DNA damage-induced pathways.
  • p53 phosphorylation at Ser-15 and Ser-392 remains unaltered in resistant cells.
  • The differential induction of p21(WAF1/CIP1) by cisplatin versus DACH-Ac-Pt in resistant cells correlates with resistance and its circumvention, highlighting the role of cyclin-dependent kinase inhibitors in differential platinum agent cytotoxicity.

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