Long associated with decreased risk of cancer, broccoli and other cruciferous vegetables — the family of plants that also includes cauliflower, cabbage, collard greens, Brussels sprouts and kale — contain a molecule that inactivates a gene known to play a role in a variety of common human cancers. In a new paper published today in Science, researchers, led by Pier Paolo Pandolfi, MD, PhD, Director of the Cancer Center and Cancer Research Institute at Beth Israel Deaconess Medical Center, demonstrate that targeting the gene, known as WWP1, with the ingredient found in broccoli suppressed tumor growth in cancer-prone lab animals.

西兰花和其他十字花科蔬菜(包括花椰菜、卷心菜、羽衣甘蓝、抱子甘蓝和羽衣甘蓝)长期以来都与降低癌症风险有关,它们含有一种分子,可以使一种已知在多种常见人类癌症中发挥作用的基因失活。在今天发表在《科学》杂志上的一篇新论文中,由医学博士、贝斯以色列女执事医疗中心癌症中心和癌症研究所主任皮埃尔·保罗·潘多尔菲领导的研究人员证明,以西兰花中发现的成分为靶点,靶向一种名为WWP1的基因,可以抑制肿瘤。

“We found a new important player that drives a pathway critical to the development of cancer, an enzyme that can be inhibited with a natural compound found in broccoli and other cruciferous vegetables,” said Pandolfi. “This pathway emerges not only as a regulator for tumor growth control, but also as an Achilles’ heel we can target with therapeutic options.”

潘德尔菲说:“我们发现了一种新的重要分子,它可以驱动癌症发展的关键途径,这种酶可以被西兰花和其他十字花科蔬菜中的一种天然化合物抑制。”“这一途径不仅作为肿瘤生长控制的调节剂出现,而且是我们可以用治疗方案瞄准的致命弱点。”

A well-known and potent tumor suppressive gene, PTEN is one of the most frequently mutated, deleted, down-regulated or silenced tumor suppressor genes in human cancers. Certain inherited PTEN mutations can cause syndromes characterized by cancer susceptibility and developmental defects. But because complete loss of the gene triggers an irreversible and potent failsafe mechanism that halts proliferation of cancer cells, both copies of the gene (humans have two copies of each gene; one from each parent) are rarely affected. Instead, tumor cells exhibit lower levels of PTEN, raising the question whether restoring PTEN activity to normal levels in the cancer setting can unleash the gene’s tumor suppressive activity.

PTEN基因是人类肿瘤中最常见的突变、缺失、下调或沉默的抑癌基因之一,是一种众所周知的高效抑癌基因。某些遗传性PTEN突变可导致以癌症易感性和发育缺陷为特征的综合征。但是,由于该基因的完全丧失会触发一种不可逆的、强有力的故障保险机制,从而阻止癌细胞的增殖,所以该基因的两个拷贝很少被影响 (人类每个基因都有两个拷贝;父母双方各提供一个)。相反,肿瘤细胞表现出较低水平的PTEN,这就提出了一个问题:在癌症环境中,将PTEN活性恢复到正常水平是否能够释放该基因的抑癌活性。

To find out, Pandolfi and colleagues identified the molecules and compounds regulating PTEN function and activation. Carrying out a series of experiments in cancer prone mice and human cells, the team revealed that a gene called WWP1 — which is also known to play a role in the development of cancer — produces an enzyme that inhibits PTEN’s tumor suppressive activity. How to disable this PTEN kryptonite? By analyzing the enzyme’s physical shape, the research team’s chemists recognized that a small molecule — formally named indole-3-carbinol (I3C), an ingredient in broccoli and its relatives — could be the key to quelling the cancer causing effects of WWP1.

为了找到答案,Pandolfi和他的同事确定了调节PTEN功能和激活的分子和化合物。研究小组在易患癌症的小鼠和人类细胞中进行了一系列实验,发现一种名为WWP1的基因会产生一种酶,抑制PTEN的抑癌活性。如何禁用这个PTEN氪星石?通过分析这种酶的物理形状,研究小组的化学家们认识到,一种名为吲哚-3-氨基酚(I3C)的小分子可能是抑制WWP1致癌效应的关键。

When Pandolfi and colleagues tested this idea by administering I3C to cancer prone lab animals, the scientists found that the naturally occurring ingredient in broccoli inactivated WWP1, releasing the brakes on the PTEN’s tumor suppressive power.

当Pandolfi和他的同事通过给癌症易感性的实验动物注射I3C来测试这个想法时,科学家们发现西兰花中天然的成分使WWP1失去活性,从而释放了PTEN抑制肿瘤的能力。

But don’t head to the farmer’s market just yet; first author Yu-Ru Lee, PhD, a member of the Pandolfi lab, notes you’d have to eat nearly 6 pounds of Brussels sprouts a day — and uncooked ones at that — to reap their potential anti-cancer benefit. That’s why the Pandolfi team is seeking other ways to leverage this new knowledge. The team plans to further study the function of WWP1 with the ultimate goal of developing more potent WWP1 inhibitors.

但先别去农贸市场;第一作者李玉茹博士是Pandolfi实验室的一名成员,她指出,为了获得潜在的抗癌益处,你必须每天吃近6磅的球芽甘蓝,而且是生的。这就是为什么Pandolfi团队正在寻找其他方法来利用这些新知识。该团队计划进一步研究WWP1的功能,最终的目标是开发更有效的WWP1抑制剂。

“Either genetic or pharmacological inactivation of WWP1 with either CRISPR technology or I3C could restore PTEN function and further unleash its tumor suppressive activity,” said Pandolfi. “These findings pave the way toward a long-sought tumor suppressor reactivation approach to cancer treatment.”

Pandolfi说:“无论是基因上还是药物上,利用CRISPR技术或I3C使WWP1失活,都可以恢复PTEN的功能,并进一步释放其肿瘤抑制活性。”“这些发现为长期寻求的肿瘤抑制因子活化疗法铺平了道路。”