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Rapamycin induces Bad phosphorylation in association with its resistance to human lung cancer cells

Yan Liu1, Shi-Yong Sun, Taofeek K Owonikoko

  • 1State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an, People's Republic of China.

Molecular Cancer Therapeutics
|November 8, 2011
PubMed

Insights

Rapamycin resistance in lung cancer involves Bad protein phosphorylation, regulated by ERK1/2 and Akt. Blocking this phosphorylation enhances rapamycin

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Rapamycin inhibits mTOR signaling, often activating ERK1/2 and Akt in cancer cells.
  • This activation can lead to resistance against rapamycin treatment.
  • The precise downstream targets of activated ERK1/2 and Akt contributing to resistance are not fully understood.

Purpose of the Study:

  • To investigate the role of Bad protein phosphorylation in rapamycin resistance in human lung cancer.
  • To elucidate the signaling pathways (ERK1/2, Akt) involved in rapamycin-induced Bad phosphorylation.
  • To explore therapeutic strategies targeting Bad phosphorylation to overcome rapamycin resistance.

Main Methods:

  • Treatment of human lung cancer cells with rapamycin.
  • Analysis of Bad protein phosphorylation at specific serine residues (S112, S136, S155).
  • Assessment of ERK1/2 and Akt activation using Western blotting and RNA interference.
  • Evaluation of Bad protein interactions (14-3-3, Bcl-XL) and degradation.
  • Inhibition of MEK/ERK pathway and Akt depletion.
  • In vitro and in vivo (xenograft) studies to assess tumor growth inhibition and antitumor efficacy.

Main Results:

  • Rapamycin treatment enhanced Bad phosphorylation at S112 and S136 in lung cancer cells, correlating with ERK1/2 and Akt activation.
  • Higher Bad phosphorylation levels were observed in rapamycin-resistant cells.
  • Rapamycin promoted Bad accumulation in the cytosol, increased Bad/14-3-3 binding, and decreased Bad/Bcl-XL binding.
  • Rapamycin-induced Bad phosphorylation accelerated its ubiquitination and degradation, reducing its half-life.
  • Inhibition of MEK/ERK or Akt blocked rapamycin-induced Bad phosphorylation.
  • Combined inhibition of Bad phosphorylation sites (S112, S136) significantly enhanced rapamycin's efficacy against lung cancer growth in vitro and in vivo.
  • Suppression of Bad phosphorylation or use of a non-phosphorylatable mutant reversed rapamycin resistance.

Conclusions:

  • Bad phosphorylation at S112 and S136, mediated by ERK1/2 and Akt, is a novel mechanism contributing to rapamycin resistance in lung cancer.
  • Targeting Bad phosphorylation represents a potential strategy to overcome rapamycin resistance.
  • Combined inhibition of Bad phosphorylation and rapamycin treatment may offer synergistic antitumor effects.

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