抑癌蛋白FOXO3a失活是发生多类肿瘤的关键

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Research Points To Forkhead Protein's Importance In Many Types Of Cancer

Two previously unconnected cancer-promoting proteins team up to ambush a critical tumor suppressor by evicting it from the cell's nucleus and then marking it for death by a protein-shredding mechanism, a team led by scientists at The University of Texas M. D. Anderson Cancer Center reports in Nature Cell Biology.

The paper is the first to illuminate a mechanism of attack on FOXO3a, a member of the forkhead family of tumor-suppressing proteins, notes senior author Mien-Chie Hung, Ph.D., chair of M. D. Anderson's Department of Molecular and Cellular Oncology.

\"We know that FOXO3a is inactivated in about 80 percent of breast tumors, and that it's likely to be inactivated in other solid tumors because three major oncogenic pathways separately target it,\" Hung said. \"The implication is that forkhead activation will be a great therapeutic target because it would be a powerful tumor-suppressor.\"

Hung and colleagues focused on the effect of the RAS-ERK signaling pathway, which is known to promote tumor growth and proliferation. FOXO3a and its other forkhead cousins have a specific structure - the forkhead box - that allows them to connect with DNA. They are transcription factors, activating or repressing target genes involved in tumor suppression and DNA damage repair.

The team shows in a series of lab experiments that ERK attaches phosphate groups to three specific sites on FOXO3a. This phosphorylated version of FOXO3a is hijacked out of the nucleus, so it can no longer do its job transcribing tumor-suppressing-genes.

Enter the second oncogenic protein, MDM2. MDM2, the team shows, only recognizes the phosphorylated version of FOXO3a. By attaching a string of targeting proteins known as ubiquitins to the phosphorylated tumor suppressor, MDM2 marks it for destruction by the ubiquitin-proteasome degradation pathway.

\"Both ERK and MDM2 are well-known oncoproteins, but their collaboration was previously unknown,\" Hung said.

In a sample of 125 breast cancer tumors, the researchers found that high MDM2 expression and low FOXO3a expression are associated with higher grade tumors.

Additional experiments showed that breast cancer cells treated with healthy FOXO3a and injected into mice resulted in barely measurable tumor volumes after 56 days. Mice injected with cells featuring a disabled version of the tumor-suppressor had an average volume of more than 600 cubic millimeters.

ERK, AKT and IKK?are three separate cancer-causing kinases - proteins that phosphorylate other proteins - that Hung calls the Three Musketeers of cancer. All three target FOXO3a. \"At least one of these pathways is active in at least 80 percent of solid tumor cancers,\" Hung says. \"ERK alone accounts for 30 percent of human cancers.\"

\"harmaceutical companies work to target ERK, AKT and IKK?separately,\" Hung notes. \"But activating their forkhead target would work against all three of them. Enhancing FOXO3a could be an effective therapeutic strategy.\"
美国德克萨斯MD Anderson肿瘤中心的一科学家团队在Nature Cell Biology上的报道称，两个早期不相关的促癌蛋白共同作用，埋伏一重要肿瘤抑制子，并将其赶出细胞核，然后通过蛋白破碎机制导致细胞死亡。

分子细胞肿瘤的MD Anderson部门主席Mien-Chie Hung博士提到，此报道是首次阐明FOXO3a的攻击机制，FOXO3a为肿瘤抑制蛋白FOXO蛋白家族中的一员。

Hung称，“我们知道，80%的乳腺癌中FOXO3a是失活的，因为3种主要致癌通路分别靶向FOXO3a，所以很可能在其他实体肿瘤中也是失活的”，“因为此蛋白可能为一重要肿瘤抑制子，这些结果提示，Fox活性将成为重要治疗靶向目标。”

Hung及其同事致力于RAS-ERK信号通路作用研究，此通路促进肿瘤生长和增殖。FOXO3a及其Fox蛋白家族蛋白的特征性结构为：forkhead box，此结构能连接DNA。他们为转录因子，能激活或抑制肿瘤抑制和DNA损伤修复基因。

科学家们经过一系列试验发现，ERK与FOXO3a的三个特异性位点的磷酸基联结。磷酸化FOXO3a被驱除出细胞核，所以此蛋白就不能转录肿瘤抑制基因。

他们指出，第二致癌蛋白MDM2仅识别磷酸化FOXO3a蛋白。MDM2将一些泛素等目标蛋白连接于磷酸化肿瘤抑制子，通过泛素蛋白酶体降解通路而将其降解。

ERK和MDM2蛋白是总所周知的癌蛋白，但是很少人研究他们之间的相互作用。
研究者做了一125例乳腺癌的试验，发现高级别肿瘤与高MDM2表达和低FOXO3a表达相关。

其他试验发现，健康FOXO3a处理过的乳腺癌细胞并将其注入小鼠体内，56天后几乎没有肿瘤生成。而将含有缺陷肿瘤抑制子的细胞注入小鼠，平均至少有600立方毫米的肿瘤生成。

ERK,AKT和IKKβ是三种独立的致癌激酶蛋白，均靶向FOXO3a，能磷酸化其它蛋白，Hung叫他们为肿瘤的三个火枪手。Hung称，至少80%的实体瘤中至少有一种通路是激活的，而仅仅ERK就占了人类肿瘤的30%.

hung指出，“制药公司分别致力于ERK，AKT和 IKKβ的研究，但是激活三者的Fox靶点，此与三者的作用均相反，增强FOXO3a可能是一有效的治疗策略。