Journal
ONCOTARGET
Volume 7, Issue 19, Pages 28329-28339Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.8631
Keywords
HDAC inhibitors; cancer stem cells; pentose phosphate pathway; G6PD
Categories
Funding
- National Institute of Health [R01CA138239-01, 1R01CA180061-01]
- Susan G. Komen Breast Cancer Foundation [KG081287]
- Morgan Welch IBC Clinic and Research Program
- State of Texas Grant for Rare and Aggressive Cancers
- University of Texas MD Anderson Cancer Center Cancer Center Support (Core) Grant from NCI/NIH [CA016672]
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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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