Histone deacetylase inhibitor-induced cancer stem cells exhibit high pentose phosphate pathway metabolism
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Bisrat G. Debeb1,5, Lara Lacerda1,5, Richard Larson1,5, Adam R. Wolfe1,5, Savitri Krishnamurthy2,5, James M. Reuben3,5, Naoto T. Ueno4,5, Michael Gilcrease2, Wendy A. Woodward1,5
1Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
2Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
3Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
4Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
5MD Anderson Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Houston, TX 77030, USA
Wendy A. Woodward, email: email@example.com
Bisrat G. Debeb, email: firstname.lastname@example.org
Keywords: HDAC inhibitors, cancer stem cells, pentose phosphate pathway, G6PD
Received: September 24, 2015 Accepted: March 16, 2016 Published: April 07, 2016
Purpose: 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.
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