ProAgio：新蛋白可能对癌症及其他疾病治疗有益

诸平

刘志仁（Zhi-Ren, LIU）教授

     据《自然通讯》（ Nature Communications）杂志报道，美国乔治亚州立大学（Georgia State University ）的研究人员设计的一种蛋白可以有效地靶向与许多疾病相关联的一种细胞表面受体，显示出治疗包括癌症在内一系列疾病的潜力，这种蛋白质被称之为ProAgio。领导此研究的是乔治亚州立大学的刘志仁（Zhi-Ren, LIU）教授。刘教授1994年从美国佛罗里达州立大学（Florida State University）获得生物化学博士学位，之后专门从事分子生物学与癌症生物学研究，旨在了解细胞异常，尤其是与许多人类疾病相关状况的分子机制。他在2011年就曾经指导过卢茵（Yin, Lu音译）的博士论文，专门研究抗血管生成蛋白质试剂的合理设计与开发，详见：Yin, Lu, "Rational Design and Development of Anti-Angiogenic Protein Agents." Dissertation, Georgia State University, 2011.此学位论文分六章共280页，其中包括参考文献414条。对于了解ProAgio的研究背景无疑具有重要参考价值。

刘教授实验室信息Lab Information

• Molecular Biology & Cancer Biology

生物通相关报道：

       ProAgio是基于一种人类蛋白而构建出来的，在其他科学家们未曾当作目标的一个新位点靶向了细胞表面受体整合素（integrin）αVβ₃。研究人员发现ProAgio可诱导表达整合素αVβ₃的细胞凋亡。这一整合素一直是药物开发的一个焦点，因为异常表达αVβ₃与许多疾病的形成及进展有关联。2012年，来自中山大学的研究人员揭示出3种与非小细胞肺癌形成、进展及预后相关的蛋白质标记物：OPN、αvβ3和Pim-1，研究论文在PLOS ONE杂志上发表（详见中山大学PLoS癌症研究新成果 ）。2014年，美国加州大学圣地亚哥医学院的研究人员发现，表面带有一种叫做整合素αvβ3生物标记物的癌细胞具有干细胞样特性且高度耐药。这项研究发现在《自然细胞生物学》（Nature Cell Biology）杂志上发表。

       刘志仁指出：“这一整合素对αVβ₃不会以高水平表达于正常组织中。在大多数情况下，它与许多不同的病理状况有关联。因此，它构成了多种疾病治疗的一个极好的靶点。” 整合素是一类细胞表面受体，在能够附着于细胞外基质的细胞中发挥至关重要的作用。它们是由不同α亚基和β亚基组合而成。不同类型的细胞有着不同的亚基对。

       许多科学家一直在研究整合素αVβ₃作为阻止炎症及新血管生长的药物的潜在靶点。这一整合素表达于新血管细胞、活化巨噬细胞，一些转移或扩散至机体其他部位的癌细胞，以及对维持和修复起关键作用的骨细胞中。以往靶向这一整合素的方法一直专注于配体结合，或将一个分子附着到这一活化位点上，但却没有取得成效。刘志仁说，当前迫切需要开发出一些药物在配体结合位点以外的位点来靶向这一整合素。“我们采用了一个独特的视角。设计了一种蛋白结合不同的位点。一旦蛋白与这一位点结合，它会直接触发细胞死亡。当我们能够杀死病变细胞时，那么我们就能消灭疾病。”

      在这项研究中，研究人员完成了大量的细胞与分子测试证实ProAgio可与整合素αVβ₃极好地互作与结合。他们发现ProAgio通过招募在程序性细胞死亡中起重要作用的酶caspase 8到整合素αVβ₃的胞质区诱导了凋亡。相比于其他测试试剂，ProAgio能够更有效地诱导细胞死亡。此外，一些癌症小鼠模型测试表明ProAgio强有力地抑制了肿瘤生长。组织分析结果表明，这一蛋白可有效阻止肿瘤血管生长，而现有血管不受影响。毒性试验也显示ProAgio对小鼠正常组织和器官是无毒的。更多信息详见：New class of protein could treat cancer and other diseases, researchers find

May 31, 2016

A protein designed by researchers at Georgia State University can effectively target a cell surface receptor linked to a number of diseases, showing potential as a therapeutic treatment for an array of illnesses, including cancer, according to the research team.

ProAgio, which is created from a human protein, targets the cell surface receptorintegrin αVβ₃ at a novel site that has not been targeted by other scientists. The researchers found ProAgio induces apoptosis, or programmed cell death, of cellsthat express integrin αVβ₃. This integrin has been a focus for drug development because abnormal expression of αVβ₃ is linked to the development and progression of a number of diseases.

The findings are reported in the journal Nature Communications.

"This integrin pair, αVβ₃, is not expressed in high levels in normal tissue," said Zhi-Ren Liu, lead author of the study and professor in the Department of Biology at Georgia State. "In most cases, it's associated with a number of different pathological conditions. Therefore, it constitutes a very good target for multiple disease treatment."

Integrins are cell surface receptors that play a critical role in cells being able to attach to the extracellular matrix. They are composed of different combinations of α and β subunits. Different types of cells have different pairs of subunits.

Integrin αVβ₃ has been studied by many scientists as a potential target for drugs that prevent inflammation and the growth of new blood vessels. This integrin is expressed in the cells of new blood vessels, activated macrophages (immune cells that are involved in the first defense against infection), some cancer cells that metastasize or spread to other parts of the body and bone cells that are critical to maintenance and repair. Previous approaches to targeting this integrin have focused on ligand binding, or attaching a molecule to the active site, which hasn't been effective. There is an urgent need to develop agents that target this integrin at sites other than the ligand-binding site, Liu said.

"We took a unique angle," Lui said. "We designed a protein that binds to a different site. Once the protein binds to the site, it directly triggers cell death. When we're able to kill pathological cells, then we're able to kill the disease."

In this study, researchers performed extensive cell and molecular testing that confirmed ProAgio interacts and binds well with integrin αVβ₃. They found ProAgio induces apoptosis by recruiting caspase 8, an enzyme that plays an essential role in programmed cell death, to the cytoplasmic area of integrin αVβ₃. ProAgio was much more effective in inducing cell death than other agents tested.

In addition, tests with mouse models of cancer showed ProAgio strongly inhibits tumor growth. Tissue analyses indicated the protein effectively prevents the growth of tumor blood vessels, while existing blood vessels were not affected. Toxicity tests also showed that ProAgio is not toxic to normal tissue and organs in mice.

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