Steroid receptor coactivator 1 is an integrator of glucose and NAD+/NADH homeostasis

Massoud Motamed, Kimal I. Rajapakshe, Sean M. Hartig, Cristian Coarfa, Robb Moses, David M. Lonard, Bert W. O'Malley

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Steroid receptor coactivator 1 (SRC-1) drives diverse gene expression programs necessary for the dynamic regulation of cancer metastasis, inflammation and gluconeogenesis, pointing to its overlapping roles as an oncoprotein and integrator of cell metabolic programs. Nutrient utilization has been intensely studied with regard to cellular adaptation in both cancer and noncancerous cells. Nonproliferating cells consume glucose through the citric acid cycle to generate NADH to fuel ATP generation via mitochondrial oxidative phosphorylation. In contrast, cancer cells undergo metabolic reprogramming to support rapid proliferation. To generate lipids, nucleotides, and proteins necessary for cell division, most tumors switch from oxidative phosphorylation to glycolysis, a phenomenon known as the Warburg Effect. Because SRC-1 is a key coactivator responsible for driving a hepatic gluconeogenic program under fasting conditions, we asked whether SRC-1 responds to alterations in nutrient availability to allow for adaptive metabolism. Here we show SRC-1 is stabilized by the 26S proteasome in the absence of glucose. RNA profiling was used to examine the effects of SRC-1 perturbation on gene expression in the absence or presence of glucose, revealing that SRC-1 affects the expression of complex I of the mitochondrial electron transport chain, a set of enzymes responsible for the conversion of NADH to NAD+. NAD+ and NADH were subsequently identified as metabolites that underlie SRC-1's response to glucose deprivation. Knockdown of SRC-1 in glycolytic cancer cells abrogated their ability to grow in the absence of glucose consistent with SRC-1's role in promoting cellular adaptation to reduced glucose availability.

Original languageEnglish (US)
Pages (from-to)395-405
Number of pages11
JournalMolecular Endocrinology
Volume28
Issue number3
DOIs
StatePublished - Mar 2014
Externally publishedYes

Fingerprint

Nuclear Receptor Coactivator 1
NAD
Homeostasis
Glucose
Oxidative Phosphorylation
Neoplasms
Electron Transport Complex I
Gene Expression
Food
Aptitude
Citric Acid Cycle
Gluconeogenesis
Oncogene Proteins
Glycolysis
Cell Division
Fasting
Nucleotides
Adenosine Triphosphate
RNA

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Cite this

Motamed, M., Rajapakshe, K. I., Hartig, S. M., Coarfa, C., Moses, R., Lonard, D. M., & O'Malley, B. W. (2014). Steroid receptor coactivator 1 is an integrator of glucose and NAD+/NADH homeostasis. Molecular Endocrinology, 28(3), 395-405. https://doi.org/10.1210/me.2013-1404

Steroid receptor coactivator 1 is an integrator of glucose and NAD+/NADH homeostasis. / Motamed, Massoud; Rajapakshe, Kimal I.; Hartig, Sean M.; Coarfa, Cristian; Moses, Robb; Lonard, David M.; O'Malley, Bert W.

In: Molecular Endocrinology, Vol. 28, No. 3, 03.2014, p. 395-405.

Research output: Contribution to journalArticle

Motamed, M, Rajapakshe, KI, Hartig, SM, Coarfa, C, Moses, R, Lonard, DM & O'Malley, BW 2014, 'Steroid receptor coactivator 1 is an integrator of glucose and NAD+/NADH homeostasis', Molecular Endocrinology, vol. 28, no. 3, pp. 395-405. https://doi.org/10.1210/me.2013-1404
Motamed, Massoud ; Rajapakshe, Kimal I. ; Hartig, Sean M. ; Coarfa, Cristian ; Moses, Robb ; Lonard, David M. ; O'Malley, Bert W. / Steroid receptor coactivator 1 is an integrator of glucose and NAD+/NADH homeostasis. In: Molecular Endocrinology. 2014 ; Vol. 28, No. 3. pp. 395-405.
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