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Oncogenic Ras differentially regulates metabolism and anoikis in extracellular matrix-detached cells

J A Mason1, C A Davison-Versagli1, A K Leliaert1

  • 1Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA.

Cell Death and Differentiation
|February 27, 2016
PubMed

Insights

Oncogenic Ras helps cancer cells survive metastasis by distinct pathways. It uses serum and glucocorticoid-regulated kinase-1 (SGK-1) to fix metabolism and blocks anoikis by reducing PHLPP1 phosphatase.

Area of Science:

  • Oncology
  • Cell Biology
  • Molecular Signaling

Background:

  • Cancer metastasis requires cells to survive extracellular matrix (ECM) detachment and anoikis (cell death).
  • Metabolic defects arise from detachment, compromising cancer cell survival during metastasis.
  • The specific signals cancer cells use to survive detachment are not fully understood.

Purpose of the Study:

  • To investigate how oncogenic Ras facilitates cancer cell survival during metastasis.
  • To identify the distinct effector pathways regulated by Ras for metabolism and anoikis.
  • To elucidate the role of phosphatidylinositol (3)-kinase signaling and its downstream effectors in anoikis resistance.

Main Methods:

  • Utilized cancer cell models to study survival mechanisms during ECM detachment.
  • Investigated oncogenic Ras signaling pathways, including phosphatidylinositol (3)-kinase (PI3K) signaling.
  • Analyzed the roles of serum and glucocorticoid-regulated kinase-1 (SGK-1), Akt, and PHLPP1 (PH Domain and Leucine-Rich Repeat Protein Phosphatase 1) in anoikis and metabolism.
  • Examined the regulation of p38 MAPK (mitogen-activated protein kinase) signaling.

Main Results:

  • Oncogenic Ras promotes survival of ECM-detached cancer cells via distinct pathways.
  • Ras-mediated PI3K signaling is crucial for correcting metabolic deficits, with SGK-1 being the key effector, not Akt.
  • Oncogenic Ras inhibits anoikis by decreasing PHLPP1 expression, which normally activates p38 MAPK.

Conclusions:

  • A novel paradigm where oncogene signaling promotes survival of detached cancer cells through divergent downstream effectors.
  • SGK-1 is identified as a critical mediator of Ras-driven metabolic adaptation during metastasis.
  • PHLPP1 downregulation by Ras is a key mechanism for blocking anoikis and promoting cancer cell survival.

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