Abstract
BackgroundAlterations in metabolism are one of the emerging hallmarks of cancer cells and targeting dysregulated cancer metabolism provides a new approach to developing more selective therapeutics. However, insufficient blockade critical metabolic dependencies of cancer allows the development of metabolic bypasses, thus limiting therapeutic benefits.MethodsA series of head and neck squamous cell carcinoma (HNSCC) cell lines and animal models were used to determine the efficacy of CPI-613 and CB-839 when given alone or in combination. Glutaminase 1 (GLS1) depletion was achieved by lentiviral shRNAs. Cell viability and apoptosis were determined in HNSCC cells cultured in 2D culture dish and SeedEZ™ 3D scaffold. Molecular alterations were examined by Western blotting and immunohistochemistry. Metabolic changes were assessed by glucose uptake, lactate production, glutathione levels, and oxygen consumption rate.ResultsWe show here that HNSCC cells display strong addiction to glutamine. CPI-613, a novel lipoate analog, redirects cellular activity towards tumor-promoting glutaminolysis, leading to low anticancer efficacy in HNSCC cells. Mechanistically, CPI-613 inhibits the tricarboxylic acid cycle by blocking the enzyme activities of pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase, which upregulates GLS1 and eventually promotes the compensatory role of glutaminolysis in cancer cell survival. Most importantly, the addition of a GLS1 inhibitor CB-839 to CPI-613 treatment abrogates the metabolic dependency of HNSCC cells on glutamine, achieving a synergistic anticancer effect in glutamine-addicted HNSCC.ConclusionsThese findings uncover the critical role of GLS1-mediated glutaminolysis in CPI-613 treatment and suggest that the CB-839 and CPI-613 combination may potentiate synergistic anticancer activity for HNSCC therapeutic gain.
Highlights
Alterations in metabolism are one of the emerging hallmarks of cancer cells and targeting dysregulated cancer metabolism provides a new approach to developing more selective therapeutics
As CPI-613 treatment resulted in significant reduction of metabolic flux through the tricarboxylic acid (TCA) cycle [7], we asked whether CPI-613 could block ATP production in head and neck squamous cell carcinoma (HNSCC) cells
This analysis identified that Glutaminase 1 (GLS1), a mitochondrial enzyme that hydrolyzes glutamine into glutamate to fuel rapid cancer cell proliferation, was the only molecule upregulated in both CPI-613-treated HN6 and HN31 cells, regardless of their growth in 2D culture dishes or SeedEZTM scaffolds (Fig. 1C-E), suggesting that glutaminolysis plays a compensatory role in cell survival upon CPI-613 treatment
Summary
Alterations in metabolism are one of the emerging hallmarks of cancer cells and targeting dysregulated cancer metabolism provides a new approach to developing more selective therapeutics. Cancer cells maintain distinctive energy metabolism networks to support and enable cell survival, growth, progression, and metastasis under harsh conditions [1, 2]. There are many metabolic pathways and processes enable cancer cells to manage metabolic stress, the lipoate-sensitive regulatory process, in. The major enzymes involved in the lipoate-sensitive regulatory process represent valuable targets for chemotherapeutic intervention [6]. CPI-613 is a novel lipoate analog that functions to inhibit tumor mitochondrial metabolism by simultaneously attacking the tricarboxylic acid (TCA) cycle enzymes pyruvate dehydrogenase (PDH) and alpha-ketoglutarate dehydrogenase (α-KGDH) [3, 7]. Whether CPI-613 exhibits anticancer potential in other types of cancer, including head and neck squamous cell carcinoma (HNSCC), has not yet been determined
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