J Exp Clin Cancer Res|Yong Teng团队在头颈癌中揭示增强CPI-613抗肿瘤功效的作用机制

2022年8月3日 0条评论 267次阅读 0人点赞

最新细胞功能及机制文献分享

目前，新陈代谢的改变已成为癌细胞的新兴标志之一，靶向失调的癌症代谢为其治疗提供了一种更具选择性的新方法。然而，对癌症关键代谢依赖性的阻断不足会导致代谢旁路的发展，从而限制靶标药物的治疗效果。2021年12月14日，美国奥古斯塔大学口腔生物学和诊断科学系Yong Teng团队在Journal of Experimental and Clinical Cancer Research上发表了题为“Blockade of glutamine-dependent cell survival augments antitumor efficacy of CPI-613 in head and neck cancer”的研究论文。在本研究中，团队通过使用一系列头颈部鳞状细胞癌（HNSCC）细胞系和动物模型，确定了CPI-613和CB-839单独或联合给药时的疗效；并采用GLS1慢病毒shRNA对HNSCC细胞系进行敲低，之后，检测细胞活力、凋亡，以及Western blot、免疫组化检测相关蛋白变化，并通过各类生化实验检测细胞中葡萄糖摄取、乳酸产生、谷胱甘肽水平和耗氧率以评估代谢变化。揭示了GLS1介导的谷氨酰胺分解在CPI-613治疗中的关键作用，并表明CB-839和CPI-613联合用药会协同增强抗癌活性，从而获得HNSCC治疗效果。

HNSCC是全球第六大流行癌症，但目前HNSCC临床治疗的预后效果不佳。研究显示，癌细胞可维持独特的能量代谢网络，以支持和促进细胞在恶劣条件下的存活、生长、进展和转移，其中，参与硫辛酸敏感调节过程的主要酶代表了化学治疗干预的重要靶点。由此，开发了代谢靶向疗法，这些疗法可靶向HNSCC恶性肿瘤所需的代谢酶和途径。据报道，CPI-613是一种新型硫辛酸酯类似物，其可通过同时攻击三羧酸（TCA）循环途径的丙酮酸脱氢酶（PDH）和α-酮戊二酸脱氢酶（α-KGDH）来抑制肿瘤线粒体代谢。癌细胞严重依赖于升高的谷氨酰胺分解代谢谷氨酰胺，进而产生ATP和乳酸以维持TCA循环功能并补偿代谢改变。谷氨酰胺在线粒体内被谷氨酰胺酶（GLS）脱氨，产生谷氨酸和氨，标志着谷氨酰胺分解的第一步，通过促进细胞增殖和抑制细胞死亡来促进肿瘤生长。在人类中，GLS家族由两个关键成员组成：GLS1和GLS2，GLS2在癌症中下调，GLS1在癌症中上调。

在本研究中，团队发现，CPI-613诱导的GLS1上调消除了HNSCC细胞（HN6、HN12、HN13、HN30和HN31）中CPI-613介导的细胞毒性。从机制上讲，CPI-613通过阻断PDH和α-KGDH的酶活来抑制TCA循环，从而上调GLS1，并最终促进谷氨酰胺分解。最重要的是，在CPI-613治疗中加入GLS1抑制剂CB-839消除了HNSCC细胞对谷氨酰胺的代谢依赖性，在谷氨酰胺依赖性HNSCC中实现了协同抗癌作用。

《J Exp Clin Cancer Res|Yong Teng团队在头颈癌中揭示增强CPI-613抗肿瘤功效的作用机制》

图药物组合介导的头颈部肿瘤生长抑制机制的示意图。

期刊及DOI号

J Exp Clin Cancer Res. 2021 Dec 14.

doi: 10.1186/s13046-021-02207-y.

题目

Blockade of glutamine-dependent cell survival augments antitumor efficacy of CPI-613 in head and neck cancer

摘要

背景：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.

方法：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.

结果：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.

结论：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.