什么是在名字？“死亡相关的蛋白质”促进最激进的乳腺癌癌细胞生长
MD安德森新闻发布2015年6月15日
MD安德森study identifies DAPK1 protein as a novel therapeutic target in tumors with TP53 mutations
MD安德森新闻Release 06/15/2015
虽然传统上理解为诱导肿瘤细胞死亡，研究人员在188bet体育网址得克萨斯大学MD安德森癌症中心的大学have discovered that the DAPK1 protein is actually essential for growth in breast and other cancers with mutations in the TP53 gene. This discovery indicates DAPK1 may be a promising new therapeutic target for many of the most aggressive cancers.
正如其名称所暗示的，DAPK1（死亡相关蛋白激酶1）在激活刺激细胞凋亡，或程序性细胞死亡，在癌细胞已经途径充分研究的作用。然而，目前的研究结果发表在该临床研究杂志，报告认为DAPK1其功能非常不同与在TP53基因（肿瘤P53蛋白）突变的癌症。
“这是以前没有集中在用于治疗癌症的研究甚少激酶，说：”Powel Brown, M.D., Ph.D.，教授和椅子，临床癌症预防, and senior author. “We discovered a yin and yang phenomenon in terms of DAPK1 function. In normal cells this protein functions as a death inducer, but in TP53 mutant cells DAPK1 acts a critical driver of cancer cell growth.”
同时寻找在侵略性乳腺癌新的治疗靶点DAPK1经鉴定，布朗解释说。雌激素受体（ER），孕酮受体（PR）和HER2：乳腺癌根据存在或不存在3种受体蛋白来分类。
Those tumors lacking ER (ER-negative), representing 30-40% of all breast cancers, are typically more aggressive and have a worse prognosis than ER-positive tumors. These also include triple receptor-negative breast cancers (TNBCs), which are particularly nasty. Unfortunately, there are few effective treatments for these tumors.
研究人员188bet体育网址发现，DAPK1在ER阴性显著上升相比，ER阳性乳腺癌。在这种积极的亚型死亡相关的蛋白质的更高水平的提出，促使进一步调查了一个难题。
虽然DAPK1水平没有出现直接受ER，DAPK1的高表达与TP53突变，这是在ER阴性乳腺癌丰富的相关成分没有显著。这是真正的特别是在TNBCs，80％或更多的怀有TP53突变。
DAPK1本身似乎是预后不良的指标。相比那些低级别DAPK1的，尤其是在患者的TP53突变的患者与高水平DAPK1的有显著较低的生存时间。
By depleting or inhibiting DAPK1 in breast cancer cell lines and mouse models, the researchers learned that cells with TP53 mutations require DAPK1 for their continued growth. Blocking DAPK1 significantly suppressed growth in TP53-mutant cells, but had no effect in those with normal TP53.
The researchers also showed that these results were mirrored in cells from other cancer types, including lung, ovarian and pancreatic, which contain mutations in TP53. As TP53 is the most commonly mutated gene across all cancer types (>50%) and is associated with a worse prognosis, DAPK1 may be a promising therapeutic target for a broad group of aggressive tumors.
“This is probably the most exciting finding,” says Brown. “While a new treatment for triple-negative breast cancers would be a major advance, DAPK1 inhibitors have the potential to be used to treat many different kinds of cancers with TP53 mutations, which include the most lethal cancers without effective treatments.”
这是在布朗的实验室研究中最活跃的地区，他渴望工作发展DAPK1抑188bet体育网址制剂作为潜在的治疗。此外，他的实验室目前正在测试DAPK1抑制结合不同类型的化疗，以确定是否添加剂好处是可以与其它靶向疗法来实现。
In fact, this is not the first protein Brown has identified with opposing roles dependent on TP53 mutations, with previous reports revealing similar behavior by thep38激酶和免疫信号蛋白TLR4。This seems to be a general phenomenon that can be taken advantage of for drug therapy, explains Brown, with little toxicity due to the dependence on TP53 mutations.
In the current study, the research team clarified the method by which DAPK1 promotes cancer growth. Their findings revealed that DAPK1 turns on a series of growth-stimulating proteins, collectively known as the mTOR pathway. Although they hypothesize that that loss of TP53 activity shifts DAPK1 activity towards the growth-promoting pathway, this regulation of DAPK1 by TP53 is unclear and is the focus of ongoing investigations.
除了布朗，其他的MD安德森作者包括：京兆，博士，临床癌症预防和分子和细胞生物学，医学，休斯敦贝勒医学院;Dekuang Zhao，博士，格雷厄姆M. Poage，博士，作者Abhijit素洁，博士，张云，贾马尔L.山和米歇尔一野人，所有临床癌症预防的;和戈登B.米尔斯，医学博士，博士，系统生物学。其他作者包括：扎卡里C.哈特曼博士，杜克大学，杜伦。
这项研究是由一个癌症中心支援津贴（CA16672），苏珊科曼无极格兰特（KG081694），第二批科曼（SAB12-00006），一个MD安德森知识沟登月补助，并从乳腺癌基金资助项目188bet体育网址研究基金会。