文章目录

胰管腺癌中谷氨酰胺拟态通过天冬酰胺代谢抑制肿瘤进展

原文发布日期：2023-10-09

英文摘要：

摘要翻译：

原文链接：

文章：

胰管腺癌中谷氨酰胺拟态通过天冬酰胺代谢抑制肿瘤进展

Glutamine mimicry suppresses tumor progression through asparagine metabolism in pancreatic ductal adenocarcinoma

原文发布日期：2023-10-09

英文摘要：

In pancreatic ductal adenocarcinoma (PDAC), glutamine is a critical nutrient that drives a wide array of metabolic and biosynthetic processes that support tumor growth. Here, we elucidate how 6-diazo-5-oxo-l-norleucine (DON), a glutamine antagonist that broadly inhibits glutamine metabolism, blocks PDAC tumor growth and metastasis. We find that DON significantly reduces asparagine production by inhibiting asparagine synthetase (ASNS), and that the effects of DON are rescued by asparagine. As a metabolic adaptation, PDAC cells upregulate ASNS expression in response to DON, and we show that ASNS levels are inversely correlated with DON efficacy. We also show that l-asparaginase (ASNase) synergizes with DON to affect the viability of PDAC cells, and that DON and ASNase combination therapy has a significant impact on metastasis. These results shed light on the mechanisms that drive the effects of glutamine mimicry and point to the utility of cotargeting adaptive responses to control PDAC progression.

摘要翻译：

在胰腺导管腺癌（PDAC）中，辅链亮氨酸是一种关键营养物质，驱动一系列代谢和合成过程，支持肿瘤生长。本研究揭示了6-二当二氮基-5-氧-乳iset的N（DON），作为一种辅链亮氨酸拮抗剂，能够广泛抑制辅链亮氨酸代谢，从而阻断PDAC肿瘤生长及转移。我们发现，DON显著降低了丙氨酸生成，这是通过抑制环丙氨酸合酶（ASNS）实现的。此外，我们也发现辅链亮氨酸利用的其他氨基酸（如谷氨酰胺）可以逆转DON的抑制作用。作为细胞代谢的一种适应性反应，在收到DON的刺激后，PDAC细胞上调了ASNS表达水平。我们还发现，位于辅链亮氨酸合成路径中的关键酶ASNS的活性与其敏感度呈现反相关性。此外，我们还发现谷丙天冬酰胺（l-asparaginase，ASNase）与DON协同作用会影响PDAC细胞的生存率，并且DON与ASNase联用疗法对转移有显著影响。这些研究为辅链亮氨酸模仿所引发的作用机制提供了新的见解，并指出通过联合靶向适应性反应可以控制PDAC进展的有效性。