Blockade of glutamine-dependent cell survival augments antitumor efficacy of CPI-613 in head and neck cancer.
Blockade of glutamine-dependent cell survival augments antitumor efficacy of CPI-613 in head and neck cancer.
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DOI：
10.1186/s13046-021-02207-y
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发表时间：
2021-12-14
期刊：
影响因子：
--
通讯作者：
Teng Y
中科院分区：
文献类型：
--
作者：
Lang L;Wang F;Ding Z;Zhao X;Loveless R;Xie J;Shay C;Qiu P;Ke Y;Saba NF;Teng Y
新陈代谢的改变是癌细胞的新特征之一，靶向失调的癌症新陈代谢为开发更具选择性的治疗方法提供了一种新的途径。然而，不充分地阻断癌症的关键代谢依赖使代谢旁路的发展，从而限制了治疗的益处。采用一系列头颈部鳞状细胞癌(HNSCC)细胞株和动物模型，研究CPI-613和CB-839单独或联合给药的疗效。通过慢病毒shRNA实现谷氨酰胺酶1(GLS1)的耗竭。在2D培养皿和SeedEZ™3D支架上培养人神经干细胞，检测细胞存活率和凋亡率。用Western blotting和免疫组织化学方法检测细胞分子变化。代谢变化通过葡萄糖摄取、乳酸生成、谷胱甘肽水平和耗氧率来评估。我们在这里显示HNSCC细胞对谷氨酰胺有强烈的成瘾。CPI-613是一种新的脂酸盐类似物，它将细胞活性重定向到促进肿瘤的谷氨酰胺分解，导致HNSCC细胞的抗癌效果较低。在机制上，CPI-613通过阻断丙酮酸脱氢酶和α-酮戊二酸脱氢酶的活性来抑制三羧酸循环，从而上调GLS1，最终促进谷氨酰胺分解对癌细胞存活的补偿作用。最重要的是，在CPI-613治疗中加入GLS1抑制剂CB-839可以消除HNSCC细胞对谷氨酰胺的代谢依赖性，在谷氨酰胺成瘾的HNSCC中实现协同抗癌作用。这些发现揭示了GLS1介导的谷氨酰胺分解在CPI-613治疗中的关键作用，并提示CB-839和CPI-613联合使用可能增强HNSCC治疗收益的协同抗癌活性。网上版载有补充材料，可在10.1186/s13046-021-02207-y查阅。
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. However, insufficient blockade critical metabolic dependencies of cancer allows the development of metabolic bypasses, thus limiting therapeutic benefits. A 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. We 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. These 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. The online version contains supplementary material available at 10.1186/s13046-021-02207-y.
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影响因子：
11.2
作者：
Galan-Cobo, Ana;Sitthideatphaiboon, Piyada;Heymach, John, V
通讯作者：
Heymach, John, V
影响因子：
5.7
作者：
Gross, Matt I.;Demo, Susan D.;Bennett, Mark K.
通讯作者：
Bennett, Mark K.
影响因子：
5.2
作者：
Bellio, Chiara;DiGloria, Celeste;Rueda, Bo R.
通讯作者：
Rueda, Bo R.
DOI：
10.1007/978-3-030-12668-1_13
发表时间：
2019-01-01
期刊：
REVIEWS ON BIOMARKER STUDIES OF METABOLIC AND METABOLISM-RELATED DISORDERS
影响因子：
--
作者：
Lang, Liwei;Chemmalakuzhy, Ron;Teng, Yong
通讯作者：
Teng, Yong
胰腺代谢扰动后胰腺癌中的代偿代谢网络。
影响因子：
16.6
作者：
Biancur DE;Paulo JA;Małachowska B;Quiles Del Rey M;Sousa CM;Wang X;Sohn ASW;Chu GC;Gygi SP;Harper JW;Fendler W;Mancias JD;Kimmelman AC
通讯作者：
Kimmelman AC