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Mutant p53-R273H mediates cancer cell survival and anoikis resistance through AKT-dependent suppression of

B S Tan1, K H Tiong2, H L Choo1

  • 11] School of Postgraduate Studies, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia [2] Center for Cancer and Stem Cell Research, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia.

Cell Death & Disease
|July 17, 2015
PubMed

Insights

Mutant p53-R273H promotes cancer cell survival by activating AKT signaling and suppressing BMF expression, leading to resistance to apoptosis. Targeting PI3K/AKT may benefit cancers with this specific p53 mutation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • p53 is a crucial tumor suppressor frequently mutated in human cancers.
  • Mutations in p53 often occur in the DNA-binding domain, producing full-length mutant proteins with altered functions.
  • Mutant p53 can gain oncogenic properties, promoting tumor development.

Purpose of the Study:

  • To investigate the specific roles of different p53 mutants (R273H and R175H) in cancer cell behavior.
  • To elucidate the molecular mechanisms by which mutant p53 influences cell survival and apoptosis.
  • To identify potential therapeutic targets in cancers harboring specific p53 mutations.

Main Methods:

  • Silencing of endogenous p53 mutants (R273H and R175H) in cancer cells.
  • Assessment of AKT phosphorylation levels.
  • Analysis of BCL2-modifying factor (BMF) and BIM expression.
  • Evaluation of resistance to anoikis (apoptosis induced by anchorage loss).
  • Investigation of the role of PI3K/AKT signaling.

Main Results:

  • Silencing p53-R273H (but not R175H) reduced AKT phosphorylation and increased BMF expression.
  • p53-R273H mutant cells exhibited resistance to anoikis and lacked BMF induction in suspension.
  • p53-R273H suppressed BMF expression via constitutively active PI3K/AKT signaling.
  • This suppression enhanced cell survival and anoikis resistance.

Conclusions:

  • The p53-R273H mutant specifically drives AKT signaling and suppresses BMF, promoting cancer cell survival and anoikis resistance.
  • These findings highlight a distinct mechanism of oncogenesis driven by the p53-R273H mutation.
  • Inhibition of PI3K/AKT signaling presents a potential therapeutic strategy for cancers expressing the p53-R273H mutant.

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