Mesothelioma cancer cells are glutamine addicted and glutamine restriction reduces YAP1 signaling to attenuate tumor formation.
Mesothelioma cancer cells are glutamine addicted and glutamine restriction reduces YAP1 signaling to attenuate tumor formation.
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DOI：
10.1002/mc.23497
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发表时间：
2023-04
影响因子：
4.6
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中科院分区：
文献类型：
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谷氨酰胺成瘾是某些类型癌症的重要表型。在这些细胞中，谷氨酰胺耗尽导致侵袭性癌症表型显著减少。间皮瘤是一种极具侵袭性的疾病，缺乏有效的治疗方法。在目前的研究中，我们表明间皮瘤是谷氨酰胺成瘾的，这表明谷氨酰胺耗竭可能是一种潜在的治疗策略。我们发现，限制谷氨酰胺，通过从培养液中去除谷氨酰胺或用抑制谷氨酰胺摄取(V-9302)或转化为谷氨酸(CB-839)的抑制剂处理，显著减少间皮瘤细胞的增殖、球体形成、侵袭和迁移。通过敲除SLC1A5谷氨酰胺转运体或用SLC1A5抑制剂V-9302治疗，也可以显著减少间皮瘤细胞肿瘤的生长。谷氨酰胺的利用与YAP1/TEAD信号通路在其他肿瘤类型中的关系已经被证明，YAP1/TEAD信号通路在间皮瘤细胞中是活跃的，并推动细胞的存活和增殖。因此，我们评估了谷氨酰胺缺乏对YAP1/TEAD信号的影响。我们发现，限制谷氨酰胺、SLC1A5基因敲除或用V-9302或CB-839处理，可以降低YAP1水平、YAP1/TEAD依赖的转录和YAP1/TEAD靶蛋白(如CTGF、细胞周期蛋白D1、COL1A2、COL3A1等)。级别。这些变化在细胞和肿瘤中都能观察到。这些发现表明间皮瘤是一种谷氨酰胺成瘾的癌症，表明谷氨酰胺缺失会减弱YAP1/TEAD信号转导和肿瘤生长，并提示限制谷氨酰胺可能是一种有用的间皮瘤治疗策略。
Glutamine addiction is an important phenotype displayed in some types of cancer. In these cells, glutamine depletion results in a marked reduction in the aggressive cancer phenotype. Mesothelioma is an extremely aggressive disease that lacks effective therapy. In the present study we show that mesothelioma tumors are glutamine addicted suggesting that glutamine depletion may be a potential therapeutic strategy. We show that glutamine restriction, by removing glutamine from the medium or treatment with inhibitors that attenuate glutamine uptake (V-9302) or conversion to glutamate (CB-839), markedly reduces mesothelioma cell proliferation, spheroid formation, invasion and migration. Inhibition of the SLC1A5 glutamine importer, by knockout or treatment with V-9302, an SLC1A5 inhibitor, also markedly reduces mesothelioma cell tumor growth. A relationship between glutamine utilization and YAP1/TEAD signaling has been demonstrated in other tumor types, and the YAP1/TEAD signaling cascade is active in mesothelioma cells and drives cell survival and proliferation. We therefore assessed the impact of glutamine depletion on YAP1/TEAD signaling. We show that glutamine restriction, SLC1A5 knockdown/knockout, or treatment with V-9302 or CB-839, reduces YAP1 level, YAP1/TEAD-dependent transcription, and YAP1/TEAD target protein (e.g., CTGF, cyclin D1, COL1A2, COL3A1, etc.) levels. These changes are observed in both cells and tumors. These findings indicate that mesothelioma is a glutamine addicted cancer, show that glutamine depletion attenuates YAP1/TEAD signaling and tumor growth, and suggests that glutamine restriction may be useful as a mesothelioma treatment strategy.
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影响因子：
--
作者：
Adhikary G;Grun D;Alexander HR;Friedberg JS;Xu W;Keillor JW;Kandasamy S;Eckert RL
通讯作者：
Eckert RL
间皮瘤患者衍生出具有定义的BAP1突变的肿瘤异种移植物，这些突变模仿了人类恶性间皮瘤的分子特征。
影响因子：
3.8
作者：
Kalra N;Zhang J;Thomas A;Xi L;Cheung M;Talarchek J;Burkett S;Tsokos MG;Chen Y;Raffeld M;Miettinen M;Pastan I;Testa JR;Hassan R
通讯作者：
Hassan R
影响因子：
2.6
作者：
Emadi, Ashkan;Ju, Sung Ah;Dang, Chi V.
通讯作者：
Dang, Chi V.
影响因子：
2.6
作者：
Boysen, Gunnar;Jamshidi-Parsian, Azemat;Griffin, Robert J.
通讯作者：
Griffin, Robert J.
影响因子：
5.7
作者：
Gross, Matt I.;Demo, Susan D.;Bennett, Mark K.
通讯作者：
Bennett, Mark K.