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 journalArticlepeer-review

22 Scopus citations

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Inhibition of AMPK and krebs cycle gene expression drives metabolic remodeling of Pten-deficient preneoplastic thyroid cells'. Together they form a unique fingerprint.

Cite this