靶向 YAP 活性和谷氨酰胺代谢可通过防止细胞外基质积累而协同抑制肿瘤进展

IF 12.5 1区 医学 Q1 ONCOLOGY Cancer research Pub Date : 2024-10-15 DOI:10.1158/0008-5472.CAN-23-3933
Mihyang Park, Jonghwa Jin, Da Young An, Dong-Ho Kim, Jaebon Lee, Jae Won Yun, Ilseon Hwang, Jae Seok Park, Mi Kyung Kim, You Mie Lee, Jun-Kyu Byun, Yeon-Kyung Choi, Keun-Gyu Park
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引用次数: 0

摘要

癌细胞利用多种机制来逃避谷氨酰胺代谢抑制剂的作用。肿瘤内谷氨酰胺可用性改变的反应途径可能是这些抑制剂组合策略的治疗目标。在这里,我们研究发现,谷氨酰胺的利用会降低环磷酸腺苷(cAMP)/蛋白激酶A(PKA)依赖的大肿瘤抑制因子(LATS)磷酸化,从而刺激癌细胞中的Yes相关蛋白(YAP)信号转导。YAP 活化的升高会增加结缔组织生长因子(CTGF)的分泌,促进周围成纤维细胞产生纤维粘连蛋白和胶原蛋白,从而诱导细胞外基质(ECM)沉积。因此,抑制 YAP 与抑制谷氨酰胺利用协同作用,可有效抑制体内肿瘤生长,同时减少 ECM 沉积。阻断 ECM 重塑也增强了谷氨酰胺利用抑制剂的抑瘤效果。总之,这些数据揭示了针对谷氨酰胺利用增加 ECM 积累的机制,并确定了降低 ECM 水平和提高谷氨酰胺代谢抑制剂疗效的潜在策略。
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Targeting YAP Activity and Glutamine Metabolism Cooperatively Suppresses Tumor Progression by Preventing Extracellular Matrix Accumulation.

Cancer cells use multiple mechanisms to evade the effects of glutamine metabolism inhibitors. The pathways that govern responses to alterations in glutamine availability within the tumor may represent therapeutic targets for combinatorial strategies with these inhibitors. Here, we showed that targeting glutamine utilization stimulated Yes-associated protein (YAP) signaling in cancer cells by reducing cyclic adenosine monophosphate/protein kinase A (PKA)-dependent phosphorylation of large tumor suppressor (LATS). Elevated YAP activation induced extracellular matrix (ECM) deposition by increasing the secretion of connective tissue growth factor that promoted the production of fibronectin and collagen by surrounding fibroblasts. Consequently, inhibiting YAP synergized with inhibition of glutamine utilization to effectively suppress tumor growth in vivo, along with a concurrent decrease in ECM deposition. Blocking ECM remodeling also augmented the tumor suppressive effects of the glutamine utilization inhibitor. Collectively, these data reveal mechanisms by which targeting glutamine utilization increases ECM accumulation and identify potential strategies to reduce ECM levels and increase the efficacy of glutamine metabolism inhibitors. Significance: Blocking glutamine utilization activates YAP to promote ECM deposition by fibroblasts, highlighting the potential of YAP inhibitors and antifibrotic strategies as promising approaches for effective combination metabolic therapies in cancer.

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来源期刊
Cancer research
Cancer research 医学-肿瘤学
CiteScore
16.10
自引率
0.90%
发文量
7677
审稿时长
2.5 months
期刊介绍: Cancer Research, published by the American Association for Cancer Research (AACR), is a journal that focuses on impactful original studies, reviews, and opinion pieces relevant to the broad cancer research community. Manuscripts that present conceptual or technological advances leading to insights into cancer biology are particularly sought after. The journal also places emphasis on convergence science, which involves bridging multiple distinct areas of cancer research. With primary subsections including Cancer Biology, Cancer Immunology, Cancer Metabolism and Molecular Mechanisms, Translational Cancer Biology, Cancer Landscapes, and Convergence Science, Cancer Research has a comprehensive scope. It is published twice a month and has one volume per year, with a print ISSN of 0008-5472 and an online ISSN of 1538-7445. Cancer Research is abstracted and/or indexed in various databases and platforms, including BIOSIS Previews (R) Database, MEDLINE, Current Contents/Life Sciences, Current Contents/Clinical Medicine, Science Citation Index, Scopus, and Web of Science.
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