L-天冬酰胺酶的谷氨酰胺酶活性介导 Asns 上调的抑制,Blood

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L-天冬酰胺酶的谷氨酰胺酶活性介导 Asns 上调的抑制
Blood ( IF 21.0 ) Pub Date : 2018-11-29 , DOI: 10.1182/blood-2018-99-117818
Wai Kin Chan ₁ , Lin Tan ₁ , Karine Harutyunyan ₂ , Di Du ₁ , Leona Martin ₁ , Eric Yin ₁ , Marina Y. Konopleva ₂ , John Weinstein ₁ , Philip L Lorenzi ₁

Affiliation

摘要 L-天冬酰胺酶 (ASNase) 是用于急性淋巴细胞白血病的治疗方案的标准成分，并且正在针对其他癌症类型进行测试，包括急性髓性白血病、淋巴瘤和胰腺癌。我们和其他人报告说，ASNase 的抗癌活性需要酶的谷氨酰胺酶活性，但导致白血病细胞死亡的潜在谷氨酰胺酶介导的机制尚不清楚。谷氨酰胺是血液中最丰富的氨基酸，以在许多生物途径中的多效作用而闻名，包括能量代谢、氧化还原代谢、核苷酸合成代谢和氨基酸合成代谢。已发现许多癌细胞会重新编程其代谢途径，从而高度依赖谷氨酰胺来生存和增殖。谷氨酰胺酶 (GLS/GLS2) 介导的谷氨酰胺向谷氨酸的转化为后者提供了通过转氨酶或谷氨酸脱氢酶 (GLUD1/GLUD2) 转化为 α-酮戊二酸的底物，为 TCA 循环提供燃料。因此，靶向谷氨酰胺代谢已成为抗癌治疗的有吸引力的策略。天冬酰胺合成酶 (ASNS) 通过合成天冬酰胺介导对 ASNase 的抗性。ASNS 在大多数细胞类型中表达，并且其表达响应于多种细胞应激而上调，包括氨基酸限制和内质网应激。我们和其他人已经表明，能够从头合成天冬酰胺的 ASNS 阳性白血病细胞对 ASNase 治疗的反应低于 ASNS 阴性白血病细胞（Chan 等人，Blood，2014）。而且，ASNase 抗性与 ASNS 表达升高有关。事实上，我们已经证明 ASNS 表达是白血病细胞系和一些实体瘤细胞类型对 ASNase 的体外反应的预测标志物。体内大多数细胞中 ASNS 的表达对 ASNase 的成功治疗提出了严峻挑战；例如，肝脏和肿瘤微环境的细胞（例如，间充质干细胞和脂肪细胞）产生天冬酰胺可能对体内的 ASNase 抗性有显着影响。在这里，我们使用高谷氨酰胺酶 E. chrysanthemi ASNase (Erwinaze®)、野生型大肠杆菌 ASNase (ASNaseWT) 和谷氨酰胺酶缺陷型大肠杆菌突变体 ASNaseQ59L 作为高、中和低-谷氨酰胺酶，分别探索ASNase谷氨酰胺酶活性介导的白血病细胞死亡机制。出乎意料的是，我们发现增加谷氨酰胺酶活性导致体外 ASNS 上调的抑制增加（图 1A）。在注射了荧光素酶标记的 Sup-B15 细胞的 NSG 小鼠中，单剂 ASNaseWT 产生了接近治愈的持久反应，而谷氨酰胺酶缺陷型 ASNaseQ59L 产生了完全反应，但会复发。总之，结果表明 ASNase 谷氨酰胺酶活性与抑制 ASNS 上调有关，从而更容易实现持久的单药抗癌活性。总体而言，这些结果为 ASNase 的作用机制提供了新的见解。披露 Konopleva：Stemline Therapeutics：研究经费。温斯坦：NIH：专利和版税：L-天冬酰胺酶。Lorenzi：Erytech Pharma：咨询；NIH：

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The Glutaminase Activity of L-Asparaginase Mediates Suppression of Asns Upregulation

Abstract L-asparaginase (ASNase) is a standard component of treatment regimens used for acute lymphoblastic leukemia and is being tested against other cancer types, including acute myeloid leukemia, lymphoma, and pancreatic cancer. We and others have reported that the anticancer activity of ASNase requires the enzyme's glutaminase activity, but the underlying glutaminase-mediated mechanism(s) that lead to leukemia cell death are unknown. Glutamine, the most abundant amino acid in the blood, is known for pleiotropic roles in numerous biological pathways, including energy metabolism, redox metabolism, nucleotide anabolism, and amino acid anabolism. Many cancer cells have been found to reprogram their metabolic pathways to become highly dependent on glutamine for survival and proliferation. Glutaminase (GLS/GLS2)-mediated conversion of glutamine to glutamic acid provides the latter as a substrate for conversion to α‐ketoglutarate by transaminases or glutamate dehydrogenases (GLUD1/GLUD2) to fuel the TCA cycle. Consequently, targeting glutamine metabolism has become an attractive strategy for anticancer therapy. The enzyme asparagine synthetase (ASNS) mediates resistance to ASNase through synthesis of asparagine. ASNS is expressed in most cell types, and its expression is upregulated in response to a wide variety of cell stresses, including amino acid limitation and endoplasmic reticulum stress. We and others have shown that ASNS-positive leukemia cells capable of synthesizing asparagine de novo are less responsive than ASNS-negative leukemia cells to ASNase therapy (Chan et al., Blood, 2014). Moreover, ASNase resistance has been associated with elevated ASNS expression. In fact, we have shown that ASNS expression is a predictive marker of the in vitro response of leukemia cell lines and some solid tumor cell types to ASNase. The expression of ASNS in most cells in the body poses a serious challenge for successful therapy with ASNase; for example, production of asparagine by the liver and cells (e.g., mesenchymal stem cells and adipocytes) of the tumor microenvironment may contribute significantly to ASNase resistance in vivo. Here we used the high-glutaminase E. chrysanthemi ASNase (Erwinaze®), wild-type E. coli ASNase (ASNaseWT), and the glutaminase-deficient E. coli mutant, ASNaseQ59L, as models of high, medium-, and low-glutaminase, respectively, to explore ASNase glutaminase activity-mediated mechanisms of leukemia cell death. Unexpectedly, we found that increasing glutaminase activity caused an increase in the suppression of ASNS upregulation in vitro (Figure 1A). In NSG mice injected with luciferase-labeled Sup-B15 cells, single-agent ASNaseWT yielded a durable response approximating cure, whereas glutaminase-deficient ASNaseQ59L yielded a complete response but with recurrence. Together, the results suggest that ASNase glutaminase activity is associated with suppression of ASNS upregulation, making durable, single-agent anticancer activity easier to achieve. Overall, the results provide new insight into the mechanism of action of ASNase. Disclosures Konopleva: Stemline Therapeutics: Research Funding. Weinstein:NIH: Patents & Royalties: L-asparaginase. Lorenzi:Erytech Pharma: Consultancy; NIH: Patents & Royalties.

更新日期：2018-11-29

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