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p85β regulates autophagic degradation of AXL to activate oncogenic signaling

Ling Rao1, Victor C Y Mak1, Yuan Zhou1

  • 1School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong.

Nature Communications
|May 10, 2020
PubMed

Insights

Amplification of PIK3R2, encoding p85β, drives ovarian cancer by increasing AXL protein. Targeting AXL or related pathways offers a new therapeutic strategy for PIK3R2-amplified cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Signaling

Background:

  • PIK3R2 amplification is common in cancers, but its role in oncogenic signaling is unclear.
  • The p85β regulatory subunit of phosphatidylinositol 3-kinase (PI3K) is implicated in cancer, yet its precise mechanisms and therapeutic relevance remain poorly understood.

Purpose of the Study:

  • To elucidate the signaling mechanisms and therapeutic implications of p85β in ovarian cancer.
  • To investigate how p85β contributes to oncogenesis and identify potential therapeutic targets.

Main Methods:

  • Investigated the effect of p85β on receptor tyrosine kinase AXL levels and downstream signaling pathways.
  • Utilized molecular biology techniques to examine the interplay between p85β, AXL, and autophagy-related proteins (TRIM2, optineurin).
  • Assessed the sensitivity of ovarian cancer cells with varying p85β expression to inhibitors of AXL, PI3K (p110), and PDK1.

Main Results:

  • p85β upregulates AXL protein levels, promoting oncogenic signaling in ovarian cancer.
  • p85β activates AKT-independent PDK1/SGK3 signaling and disrupts autophagic degradation of AXL via TRIM2 and optineurin.
  • p85β expression sensitizes ovarian cancer cells to AXL, p110, or PDK1 inhibitors, while p85β depletion reduces sensitivity.

Conclusions:

  • p85β drives ovarian cancer progression by stabilizing AXL and activating specific signaling pathways.
  • Pharmacological inhibition of the AXL signaling axis is a promising therapeutic strategy for PIK3R2-amplified ovarian cancers.
  • Understanding the p85β-AXL interaction provides a rationale for targeted therapies in specific cancer subtypes.

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