B7-H3 Associates with IMPDH2 and Regulates Cancer Cell Survival.
B7-H3 Associates with IMPDH2 and Regulates Cancer Cell Survival.
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B7-H3 与 IMPDH2 相关并调节癌细胞存活。
作者：
肺癌是世界上最常见的癌症之一，尽管治疗有所改善，但它仍然是一个重大的健康负担。B7-H3是膜蛋白的B7免疫检查点家族的成员，并且在肺癌中显示出增加的表达;然而，这对癌细胞信号传导的功能后果仍然不清楚。在这里，我们表明B7-H3与代谢酶IMPDH 2形成复合物，这可以保护癌细胞免受氧化应激和化疗引发的细胞凋亡。在2D中从癌细胞中去除B7-H3导致对化疗应激的敏感性，并以IMPDH 2依赖性方式降低细胞活力。然而，3D球体模型中B7-H3的损失导致增强的IMPDH 2依赖性球体生长，这可能是由于细胞-细胞粘附的减弱。这些发现表明，B7-H3在不存在免疫细胞相互作用的情况下在功能上有助于肺癌细胞中的代谢信号传导。肺癌是全球最常见的癌症之一，尽管治疗方案有所改进，但患者预后仍然很差。肺腺癌从肺上皮细胞发展而来，了解特定的遗传和环境因素如何导致这些细胞中的致癌转化对于确定有助于肿瘤发生的途径非常重要。最近使用免疫疗法治疗不同癌症的兴起，促使人们探索肿瘤细胞中的免疫调节剂，这可能为操纵这一过程提供新的靶点。其中，B7家族的细胞表面受体，包括PD-1，由于其在调节肿瘤微环境内的免疫细胞反应中的作用而特别令人感兴趣。B7-H3（CD 276）是一个在许多癌症类型中上调的家族成员，并被认为有助于肿瘤-免疫相互作用。然而，该受体在正常肺上皮中的功能和配体以及B7-H3的过表达在缺乏免疫细胞相互作用的情况下调节癌症进展的机制仍然不清楚。在这里，我们提出的证据表明，B7-H3与一种关键的限速代谢酶IMPDH 2相关，并且这种复合物的定位在表达高水平B7-H3的人肺癌细胞中发生了改变。从机制上讲，IMPDH 2：B7-H3复合物在癌细胞中提供保护作用，以逃避化疗引发的氧化应激，从而导致细胞存活。我们进一步证明，癌细胞中B7-H3的丢失对2D中的生长或迁移没有影响，但以IMPDH 2依赖性方式促进3D球状体的扩张。这些发现为B7-H3在正常和转化肺癌细胞的代谢稳态中的功能提供了新的见解，虽然这种分子仍然是免疫治疗的有趣靶点，但这些发现警告在某些临床环境中使用抗B7-H3疗法。
Lung cancer is one of the most common cancers in the world, and despite improvements in treatment, it remains a significant health burden. B7-H3 is a member of the B7 immune checkpoint family of membrane proteins and shows increased expression in lung cancers; however, the functional consequences of this to cancer cell signalling remain unclear. Here, we show that B7-H3 forms a complex with the metabolic enzyme IMPDH2, and this protects cancer cells from oxidative stress and resulting apoptosis triggered by chemotherapy. The removal of B7-H3 from cancer cells in 2D results in sensitisation to chemotherapeutic stress and reduces cell viability in an IMPDH2-dependent manner. However, the loss of B7-H3 in 3D spheroid models results in enhanced IMPDH2-dependent spheroid growth, likely due to the weakening of cell–cell adhesion. These findings demonstrate that B7-H3 functionally contributes to metabolic signalling in lung cancer cells in the absence of immune cell interactions. Lung cancer is one of the most common cancers worldwide, and despite improvements in treatment regimens, patient prognosis remains poor. Lung adenocarcinomas develop from the lung epithelia and understanding how specific genetic and environmental factors lead to oncogenic transformation in these cells is of great importance to define the pathways that contribute to tumorigenesis. The recent rise in the use of immunotherapy to treat different cancers has prompted the exploration of immune modulators in tumour cells that may provide new targets to manipulate this process. Of these, the B7 family of cell surface receptors, which includes PD-1, is of particular interest due to its role in modulating immune cell responses within the tumour microenvironment. B7-H3 (CD276) is one family member that is upregulated in many cancer types and suggested to contribute to tumour–immune interactions. However, the function and ligand(s) for this receptor in normal lung epithelia and the mechanisms through which the overexpression of B7-H3 regulate cancer progression in the absence of immune cell interactions remain unclear. Here, we present evidence that B7-H3 is associated with one of the key rate-limiting metabolic enzymes IMPDH2, and the localisation of this complex is altered in human lung cancer cells that express high levels of B7-H3. Mechanistically, the IMPDH2:B7-H3 complex provides a protective role in cancer cells to escape oxidative stress triggered by chemotherapy, thus leading to cell survival. We further demonstrate that the loss of B7-H3 in cancer cells has no effect on growth or migration in 2D but promotes the expansion of 3D spheroids in an IMPDH2-dependent manner. These findings provide new insights into the B7-H3 function in the metabolic homeostasis of normal and transformed lung cancer cells, and whilst this molecule remains an interesting target for immunotherapy, these findings caution against the use of anti-B7-H3 therapies in certain clinical settings.
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作者：
Barfeld SJ;Fazli L;Persson M;Marjavaara L;Urbanucci A;Kaukoniemi KM;Rennie PS;Ceder Y;Chabes A;Visakorpi T;Mills IG
通讯作者：
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作者：
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通讯作者：
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Carcamo WC;Satoh M;Kasahara H;Terada N;Hamazaki T;Chan JY;Yao B;Tamayo S;Covini G;von Mühlen CA;Chan EK
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细胞外嘌呤，嘌呤能受体和肿瘤生长。
影响因子：
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作者：
Di Virgilio F;Adinolfi E
通讯作者：
Adinolfi E