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Involvement of transforming growth factor-beta 1 signaling in hypoxia-induced tolerance to glucose starvation

Atsushi Suzuki1, Gen-ichi Kusakai, Yosuke Shimojo

  • 1Cancer Physiology Project, National Cancer Center Research Institute East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan.

The Journal of Biological Chemistry
|July 15, 2005
PubMed

Insights

Hypoxia protects human hepatoma cells from glucose starvation-induced death by activating AMP-activated protein kinase-alpha (AMPK-alpha) and the Akt/ARK5 system. This tolerance is mediated by hypoxia-induced transforming growth factor-beta 1 (TGF-beta1).

Area of Science:

  • Oncology
  • Cell Biology
  • Biochemistry

Background:

  • Human hepatoma cell survival depends on nutrients like glucose.
  • Glucose starvation triggers rapid cell death in hepatoma cells.
  • Hypoxia significantly suppresses this cell death, a phenomenon we term hypoxia-induced tolerance.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying hypoxia-induced tolerance in HepG2 human hepatoma cells.
  • To investigate the roles of AMP-activated protein kinase-alpha (AMPK-alpha), Akt, and ARK5 in this process.
  • To determine the involvement of transforming growth factor-beta (TGF-beta) signaling.

Main Methods:

  • Investigated protein kinase phosphorylation (AMPK-alpha, Akt) under glucose starvation and hypoxia.
  • Utilized gene silencing (AMPK-alpha) and pharmacological inhibitors (Akt/ARK5 system, TGF-beta receptor) to assess pathway contributions.
  • Quantified TGF-beta1 mRNA expression and its effect on cell viability.
  • Assessed activation of AMPK-alpha, Akt, and ARK5 by TGF-beta1.

Main Results:

  • Hypoxia prolonged glucose starvation-induced phosphorylation of Akt and AMPK-alpha.
  • Blocking the Akt/ARK5 system or suppressing AMPK-alpha partially abrogated tolerance; combined suppression abolished it.
  • Hypoxia induced TGF-beta1 expression independently of hypoxia-inducible factor-1alpha.
  • TGF-beta1 addition suppressed cell death, and TGF-beta1 activated AMPK-alpha, Akt, and ARK5.

Conclusions:

  • AMPK-alpha activation signaling and the Akt/ARK5 system are independently essential for hypoxia-induced tolerance.
  • Hypoxia-induced TGF-beta1 plays a critical role in mediating this tolerance.
  • The proposed mechanism involves hypoxia-induced TGF-beta1 activating both AMPK-alpha and the Akt/ARK5 pathway, conferring tumor cell tolerance to glucose starvation.

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