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PHLDA2 is a key oncogene-induced negative feedback inhibitor of EGFR/ErbB2 signaling via interference with AKT

Xiaoqi Wang1, Guangyuan Li1,2, Sanjay Koul1

  • 1Division of Hematology/Oncology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA.

Oncotarget
|June 5, 2018
PubMed

Insights

Pleckstrin homology-like domain family A member 2 (PHLDA2) suppresses lung cancer growth by inhibiting AKT pathway activation, acting as a biomarker for this signaling cascade. PHLDA2 is induced by oncogenic EGFR/ErbB2 signaling.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Signaling

Background:

  • Pleckstrin homology-like domain family A member 2 (PHLDA2) is a tumor suppressor gene. Its expression is reduced in various cancers.
  • Epidermal Growth Factor Receptor (EGFR) and ErbB2 signaling pathways are frequently dysregulated in cancers, driving tumor growth.
  • The AKT pathway is a critical mediator of cell survival and proliferation in cancer.

Purpose of the Study:

  • To investigate the role of PHLDA2 in lung cancer.
  • To determine the relationship between PHLDA2, EGFR/ErbB2 signaling, and AKT activation.
  • To explore PHLDA2 as a potential biomarker for AKT pathway activation in lung cancer.

Main Methods:

  • Immunohistochemical analysis of PHLDA2 and AKT activation in human lung cancer tissues.
  • In vitro studies to assess the effects of PHLDA2 overexpression and knockdown on AKT phosphorylation and activity.
  • Cellular assays to evaluate PHLDA2's impact on anchorage-independent growth, proliferation, and sensitivity to targeted therapies.

Main Results:

  • PHLDA2 expression positively correlates with AKT activation in lung cancers.
  • PHLDA2 overexpression inhibits AKT phosphorylation and membrane translocation, while PHLDA2 knockdown enhances AKT activity.
  • PHLDA2 overexpression suppresses anchorage-independent growth, and its decreased expression increases proliferation and reduces sensitivity to EGFR/ErbB2-targeted agents.

Conclusions:

  • PHLDA2 is a downstream target of oncogenic EGFR/ErbB2 signaling and negatively regulates AKT activation in lung cancer.
  • PHLDA2 acts as a direct inhibitor of AKT by competing for membrane lipid binding, thus repressing cell proliferation.
  • PHLDA2 serves as a potential biomarker for AKT pathway activation and a therapeutic target in EGFR/ErbB2-driven lung cancers.
Keywords:
AKTEGFRErbB2PHLDA2

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