Activation of the Akt survival pathway contributes to TRAIL resistance in cancer cells

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Jing Xu1, Jun-Ying Zhou, Wei-Zen Wei

  • 1Program in Molecular Biology & Genetics, Karmanos Cancer Institute, Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan, United States of America.

Plos One
|April 27, 2010
PubMed

Insights

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance in cancer is linked to the Akt survival pathway. Targeting PTEN or Akt can overcome this resistance, enhancing cancer cell apoptosis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Signaling

Background:

  • The mechanisms underlying tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance in cancer cells remain incompletely understood.
  • TRAIL is a critical protein involved in initiating programmed cell death (apoptosis) in various cancer types.
  • Understanding resistance mechanisms is crucial for developing effective cancer therapies.

Purpose of the Study:

  • To elucidate the role of the Akt survival pathway in TRAIL resistance.
  • To investigate the relationship between PTEN, Akt, and TRAIL sensitivity.
  • To identify potential therapeutic strategies to overcome TRAIL resistance.

Main Methods:

  • Investigated the effect of TRAIL treatment on Akt activation in human cancer cells.
  • Utilized PI3K inhibitor LY294002 and Akt knockdown to assess pathway inhibition.
  • Examined TRAIL sensitivity in PTEN knockdown and knockout mouse prostate epithelial cells.
  • Assessed the impact of PTEN overexpression on TRAIL sensitivity in cancer cells.

Main Results:

  • TRAIL treatment activates the pro-survival Akt pathway in cancer cells.
  • Inhibition of the Akt pathway sensitizes resistant cancer cells to TRAIL.
  • Loss or reduced function of the tumor suppressor PTEN leads to increased TRAIL resistance.
  • Overexpression of mutant PTEN confers TRAIL resistance, highlighting PTEN's role.

Conclusions:

  • Inactivation of PTEN and subsequent Akt pathway activation contribute significantly to TRAIL resistance.
  • Targeting the PTEN/Akt axis presents a promising strategy to overcome TRAIL resistance in cancer.
  • Restoring PTEN function or inhibiting Akt may re-sensitize resistant tumors to TRAIL-based therapies.

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