title: Histone deacetylase inhibitor-induced cancer stem cells exhibit high pentose phosphate pathway metabolism.
abstract: OBJECTIVE
  We recently demonstrated that histone deacetylase (HDAC) inhibitors can "reprogram" differentiated triple-negative breast cancer cells to become quiescent stem-like cancer cells. We hypothesized that the metabolic state of such cells differs from that of their differentiated progeny.
  
  
  RESULTS
  In untreated cells, glucose uptake was higher in ALDH+ cells than in ALDH- cells (p = 0.01) but lactate production was not different; treating ALDH- or ALDH+ cells with VA or SAHA similarly increased glucose uptake without changing lactate production but upregulated G6PD, a rate-limiting enzyme in pentose phosphate pathway metabolism. NADPH production was higher in HDAC inhibitor-treated stem-like cells than in vehicle-treated cells (p < 0.05). Two G6PD inhibitors, 6-aminonicotinamide and dehydroepiandrosterone, decreased mammosphere formation efficiency and ALDH activity and 6-aminonicotinamide reduced the VA-induced increase in ALDH+ cells. Finally, patients expressing high G6PD mRNA had significantly worse overall survival (p < 0.001), and patients with high G6PD protein showed a similar trend towards worse disease-specific survival (p = 0.06).
  
  
  METHODS
  Glucose consumption, lactate and NADPH production, and reactive oxygen species generation were compared in aldehyde dehydrogenase (ALDH)-positive and -negative cells in the presence or absence of the HDAC inhibitors valproic acid (VA) or suberoylanilide hydroxamic acid (SAHA). Glucose-6-phosphate dehydrogenase (G6PD) expression was evaluated in a tissue microarray from 94 patients with node-positive invasive breast carcinoma and in two publically available databases and correlated with overall survival.
  
  
  CONCLUSIONS
  Energy metabolism in HDAC inhibitor-induced stem-like cancer cells differed sharply from that of differentiated cell types. HDAC inhibitor-induced dedifferentiation promoted metabolic reprogramming into the pentose phosphate pathway, which is targeted effectively by G6PD inhibition. These findings highlight a potential dual-therapy approach to targeting bulk differentiated cells with HDAC inhibitors and CSCs with G6PD inhibitors.
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|MD Anderson Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Houston, TX 77030, USA.
authors.forename: Bisrat G
authors.initials: BG
authors.lastname: Debeb
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|MD Anderson Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Houston, TX 77030, USA.
authors.forename: Lara
authors.initials: L
authors.lastname: Lacerda
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|MD Anderson Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Houston, TX 77030, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Larson
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|MD Anderson Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Houston, TX 77030, USA.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Wolfe
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|MD Anderson Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Houston, TX 77030, USA.
authors.forename: Savitri
authors.initials: S
authors.lastname: Krishnamurthy
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|MD Anderson Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Houston, TX 77030, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Reuben
authors.affiliation: Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|MD Anderson Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Houston, TX 77030, USA.
authors.forename: Naoto T
authors.initials: NT
authors.lastname: Ueno
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Gilcrease
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|MD Anderson Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Houston, TX 77030, USA.
authors.forename: Wendy A
authors.initials: WA
authors.lastname: Woodward
mesh_terms: D054337:Cell Dedifferentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D005260:Female; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism*; D010427:Pentose Phosphate Pathway / Q000187:drug effects; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism* / Q000473:pathology
chemical_list: D056572:Histone Deacetylase Inhibitors; D005954:Glucosephosphate Dehydrogenase
keywords: G6PD; HDAC inhibitors; cancer stem cells; pentose phosphate pathway