Inhibition of AMPK and krebs cycle gene expression drives metabolic remodeling of Pten-deficient preneoplastic thyroid cells

Valeria G. Antico Arciuch, Marika A. Russo, Kristy S. Kang, Antonio Di Cristofano

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Rapidly proliferating and neoplastically transformed cells generate the energy required to support rapid cell division by increasing glycolysis and decreasing flux through the oxidative phosphorylation (OXPHOS) pathway, usually without alterations in mitochondrial function. In contrast, little is known of the metabolic alterations, if any, which occur in cells harboring mutations that prime their neoplastic transformation. To address this question, we used a Pten-deficient mouse model to examine thyroid cells where a mild hyperplasia progresses slowly to follicular thyroid carcinoma. Using this model, we report that constitutive phosphoinositide 3-kinase (PI3K) activation caused by PTEN deficiency in nontransformed thyrocytes results in a global downregulation of Krebs cycle and OXPHOS gene expression, defective mitochondria, reduced respiration, and an enhancement in compensatory glycolysis. We found that this process does not involve any of the pathways classically associated with the Warburg effect. Moreover, this process was independent of proliferation but contributed directly to thyroid hyperplasia. Our findings define a novel metabolic switch to glycolysis driven by PI3K-dependent AMPK inactivation with a consequent repression in the expression of key metabolic transcription regulators.

Original languageEnglish (US)
Pages (from-to)5459-5472
Number of pages14
JournalCancer Research
Volume73
Issue number17
DOIs
StatePublished - Sep 1 2013

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AMP-Activated Protein Kinases
Citric Acid Cycle
Glycolysis
Thyroid Gland
1-Phosphatidylinositol 4-Kinase
Oxidative Phosphorylation
Gene Expression
Hyperplasia
Follicular Adenocarcinoma
Cell Division
Mitochondria
Respiration
Down-Regulation
Mutation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Inhibition of AMPK and krebs cycle gene expression drives metabolic remodeling of Pten-deficient preneoplastic thyroid cells. / Antico Arciuch, Valeria G.; Russo, Marika A.; Kang, Kristy S.; Di Cristofano, Antonio.

In: Cancer Research, Vol. 73, No. 17, 01.09.2013, p. 5459-5472.

Research output: Contribution to journalArticle

Antico Arciuch, Valeria G. ; Russo, Marika A. ; Kang, Kristy S. ; Di Cristofano, Antonio. / Inhibition of AMPK and krebs cycle gene expression drives metabolic remodeling of Pten-deficient preneoplastic thyroid cells. In: Cancer Research. 2013 ; Vol. 73, No. 17. pp. 5459-5472.
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