Cancer stem cells from epithelial ovarian cancer patients privilege oxidative phosphorylation, and resist glucose deprivation

TLDR

Cancer stem cells from epithelial ovarian cancer patients were studied to characterize their metabolic profile. These CSCs exhibited a metabolic program dominated by oxidative phosphorylation, with upregulated glucose uptake, fatty‑acid oxidation, and pentose‑phosphate pathway activity, higher mitochondrial ROS and membrane potential, and resistance to glucose deprivation that led to apoptosis only when the respiratory chain was inhibited, suggesting a mechanism for their anti‑angiogenic therapy resistance and a potential therapeutic target.

Abstract

// Anna Pastò 1,* , Chiara Bellio 1,* , Giorgia Pilotto 1,* , Vincenzo Ciminale 1,2 , Micol Silic-Benussi 2 , Giulia Guzzo 3 , Andrea Rasola 3 , Chiara Frasson 4 , Giorgia Nardo 2 , Elisabetta Zulato 2 , Maria Ornella Nicoletto 2 , Mariangela Manicone 2 , Stefano Indraccolo 2,* and Alberto Amadori 1,2,* 1 Department of Surgery, Oncology, and Gastroenterology, Oncology Section, University of Padova, Padova, Italy 2 Istituto Oncologico Veneto-IRCCS (IOV), Padova, Italy 3 Department of Biomedical Sciences, University of Padova, Padova, Italy 4 Department of Woman and Child Health, Laboratory of Hemato-Oncology, University of Padova, Padova, Italy * These Authors contributed equally to this work Correspondence: Alberto Amadori, email: // Keywords : Ovarian cancer, Cancer Stem Cells, metabolism, glucose, Warburg effect Received : February 27, 2014 Accepted : May 24, 2014 Published : May 26, 2014 Abstract We investigated the metabolic profile of cancer stem cells (CSC) isolated from patients with epithelial ovarian cancer. CSC overexpressed genes associated with glucose uptake, oxidative phosphorylation (OXPHOS), and fatty acid β-oxidation, indicating higher ability to direct pyruvate towards the Krebs cycle. Consistent with a metabolic profile dominated by OXPHOS, the CSC showed higher mitochondrial reactive oxygen species (ROS) production and elevated membrane potential, and underwent apoptosis upon inhibition of the mitochondrial respiratory chain. The CSC also had a high rate of pentose phosphate pathway (PPP) activity, which is not typical of cells privileging OXPHOS over glycolysis, and may rather reflect the PPP role in recharging scavenging enzymes. Furthermore, CSC resisted in vitro and in vivo glucose deprivation, while maintaining their CSC phenotype and OXPHOS profile. These observations may explain the CSC resistance to anti-angiogenic therapies, and indicate this peculiar metabolic profile as a possible target of novel treatment strategies.