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西蘭花中發現的天然化合物能喚醒強大的腫瘤抑制功能 精選

已有 2468 次閱讀 2019-5-20 08:52 |個人分類:飲食與健康|系統分類:科普集錦| 西蘭花, I3C, WWP1, PTEN, 腫瘤抑制活性

西蘭花中發現的天然化合物能喚醒強大的腫瘤抑制功能

諸平


貝斯以色列女執事醫療中心

貝斯以色列女執事醫療中心(Beth Israel Deaconess Medical Center,簡稱BIDMC)是一個位于美國馬薩諸塞州波士頓的國際知名醫療中心,是哈佛醫學院主要的教學醫院。它的前身是“貝斯以色列醫院1916年成立)和新英格蘭女執事醫院1896年成立),1996年兩所醫院合并。在獨立的教學醫院中,貝斯以色列女執事醫療中心從美國國家衛生研究院(National Institutes of Health, NIH)所接受的生物醫學研究資金名列第三位,每年接近1.5億美元。貝斯以色列女執事醫療中心的研究人員超過1000名。貝斯以色列女執事醫療中心坐落在長木醫學區,是馬薩諸塞Caregroup Healthcare System的旗艦醫院,一向被美國U.S. News & World Report列為美國最好的醫院之一。它是新英格蘭最大的醫院之一,僅次于均位于波士頓的麻省總醫院(Massachusetts General Hospital;Mass GeneralMGH)布萊根婦女醫院(Brigham and Women's Hospital,BWH)。 貝斯以色列女執事醫療中心發展史上的里程碑是1922年在英格蘭首次注射胰島素以及1960年首次植入心臟起搏器。該醫療中心2019年5月17日在《科學》(Science)雜志網站發表文章指出,西蘭花中的天然產物能夠喚醒強大的腫瘤抑制功能——Yu-Ru Lee, Ming Chen, Jonathan D. Lee, Jinfang Zhang, Shu-Yu Lin, Tian-Min Fu, Hao Chen, Tomoki Ishikawa, Shang-Yin Chiang, Jesse Katon, Yang Zhang, Yulia V. Shulga, Assaf C. Bester, Jacqueline Fung, Emanuele Monteleone, Lixin Wan, Chen Shen, Chih-Hung Hsu, Antonella Papa, John G. Clohessy, Julie Teruya-Feldstein, Suresh Jain, Hao Wu, Lydia Matesic, Ruey-Hwa Chen, Wenyi Wei, Pier Paolo Pandolfi. Reactivation of PTEN tumor suppressor for cancer treatment through inhibition of a MYC-WWP1 inhibitory pathway. Science, 17 May 2019: Vol. 364, Issue 6441, eaau0159. DOI: 10.1126/science.aau0159

西蘭花

媽媽會經常告訴孩子,西蘭花對你的健康有好處。西蘭花和其他十字花科植物,包括花椰菜、卷心菜、羽衣甘藍、抱子甘藍和甘藍等,長期以來都與降低患癌癥的風險有關。這些十字花科植物含有一種分子,可以使一種已知在多種常見人類癌癥中發揮作用的基因失去活性。2019517日發表于《科學》雜志的一篇新論文,由美國哈佛醫學院貝斯以色列女執事醫療中心癌癥中心癌癥研究所(Cancer Research Institute, Beth Israel Deaconess Cancer Center, Harvard Medical School)主任Pier Paolo Pandolfi博士,與來自美國、印度、意大利、澳大利亞、中國浙江大學醫學院和臺灣大學生命科學院生化科學研究所、臺灣中央研究院生化研究所的科研人員合作完成,表明目標基因-WWP1, 西蘭花中發現的成分能夠抑制癌變實驗室動物的腫瘤生長。

Pier Paolo Pandolfi博士說:“我們發現了一種新的重要分子,它可以驅動癌癥發展的關鍵途徑,這種酶可以被西蘭花和其他十字花科蔬菜中的一種天然化合物抑制。”“這一途徑不僅作為腫瘤生長控制的調節劑出現,而且是我們可以用治療方案瞄準的致命弱點。

PTEN基因是人類腫瘤中最常見的突變、缺失、下調或沉默的抑癌基因之一,是一種眾所周知的高效抑癌基因。某些遺傳性PTEN突變可導致以癌癥易感性和發育缺陷為特征的綜合癥。但是,由于該基因的完全喪失會觸發一種不可逆的、強有力的故障保險機制,從而阻止癌細胞的增殖,所以該基因的兩個拷貝(人類每個基因都有兩個拷貝;來自父母雙方的一個)很少被影響。相反,腫瘤細胞表現出較低水平的PTEN,這就提出了一個問題:在癌癥環境中,將PTEN活性恢復到正常水平是否能夠釋放該基因的抑癌活性。為了找到答案,Pier Paolo Pandolfi博士和他的同事確定了調節PTEN功能和激活的分子和化合物。研究小組在易患癌癥的小鼠和人類細胞中進行了一系列實驗,發現一種名為WWP1的基因會產生一種酶,抑制PTEN的抑癌活性。如何禁用這個PTEN的克星?就是需要研究解決的難題。通過分析這種酶的物理形狀,研究小組的化學家們認識到,一種名為吲哚-3-甲醇(indole-3-carbinol, I3C)的小分子可能是抑制WWP1致癌作用的關鍵。吲哚-3-甲醇是西蘭花及其十字花科蔬菜中一種主要的有效植物化學物質,具有防癌和抗癌作用。

Pier Paolo Pandolfi博士和他的同事通過給易患癌癥的實驗動物注射I3C來測試這個想法時,科學家們發現西蘭花中天然的成分使WWP1失去活性,從而釋放了PTEN抑制腫瘤的能力。

先別忙著去農貿市場購買西蘭花等十字花科蔬菜;第一作者李玉儒(Yu-Ru Lee音譯)博士是Pier Paolo Pandolfi實驗室的成員,他指出,為了獲得潛在的抗癌益處,你必須每天吃近6磅的球芽甘藍——而且是生的。這就是為什么Pier Paolo Pandolfi研究團隊正在尋找其他方法來利用這些新知識的原因。該團隊計劃進一步研究WWP1的功能,最終的目標是開發更有效的WWP1抑制劑。

Pier Paolo Pandolfi博士說:“無論是基因上還是藥物上,利用CRISPR技術或I3C使WWP1失活,都可以恢復PTEN的功能,并進一步釋放其腫瘤抑制活性。”“這些發現為長期尋求的腫瘤抑制因子活化療法鋪平了道路。 更多信息請注意瀏覽原文或者相關報道。

Abstract

Activation of tumor suppressors for the treatment of human cancer has been a long sought, yet elusive, strategy. PTEN is a critical tumor suppressive phosphatase that is active in its dimer configuration at the plasma membrane. Polyubiquitination by the ubiquitin E3 ligase WWP1 (WW domain–containing ubiquitin E3 ligase 1) suppressed the dimerization, membrane recruitment, and function of PTEN. Either genetic ablation or pharmacological inhibition of WWP1 triggered PTEN reactivation and unleashed tumor suppressive activity. WWP1 appears to be a direct MYC (MYC proto-oncogene) target gene and was critical for MYC-driven tumorigenesis. We identified indole-3-carbinol, a compound found in cruciferous vegetables, as a natural and potent WWP1 inhibitor. Thus, our findings unravel a potential therapeutic strategy for cancer prevention and treatment through PTEN reactivation.

Supporting tumor suppression

The protein PTEN is a phosphatase and tumor suppressor whose activity is often decreased in human cancers. Thus, reactivating such a protein could potentially be an effective therapy against cancer. Lee et al. identified a ubiquitin E3 ligase (WWP1) as a PTEN-interacting protein that modifies PTEN and inhibits its tumor suppressive activity (see the Perspective by Parsons). Depletion of WWP1 increased dimerization and membrane recruitment of PTEN. A natural compound found to be a pharmacological inhibitor of WWP1 inhibited tumor growth in a mouse model of prostate cancer. Thus, reactivation of the tumor suppressor PTEN may provide a strategy for battling tumors.

Science, this issue p. eaau0159; see also p. 633

Structured Abstract

INTRODUCTION

Inhibition of oncogenic proteins represents a mainstay approach for cancer therapeutic development. By contrast, pharmacological modulation of tumor suppressor activity for the treatment of cancer has remained elusive. PTEN is a potent tumor suppressor gene, antagonizing the proto-oncogenic phosphoinositide 3-kinase (PI3K)–AKT signaling pathway and governing fundamental cellular processes. Cancer cells cannot afford to lose complete PTEN activity prematurely, because this would trigger cellular senescence, making PTEN an “obligate haploinsufficient” tumor suppressor gene. For this reason, PTEN is frequently dysregulated through monoallelic loss, aberrant subcellular localization, and/or posttranslational modification in human cancers as well as in cancer susceptibility syndromes such as PTEN hamartoma tumor syndrome (PHTS). Because PTEN overexpression in mice results in a tumor-suppressive metabolic state and life-span extension, the identification of molecular mechanisms to activate and reactivate PTEN function would offer important therapeutic opportunities for human health.

RATIONALE

Although PTEN dimer formation and recruitment at the plasma membrane are indispensable for its function and activation, the mechanisms regulating these processes remain unknown. We thus sought to identify upstream regulators of PTEN dimerization and membrane localization, inhibition of which may restore PTEN activity and provide therapeutic opportunities against cancer.

RESULTS

Through immunoprecipitation followed by mass spectrometry analysis, we identified the HECT-type E3 ubiquitin ligase WWP1 as a physical PTEN interactor. We found that WWP1 specifically triggers nondegradative K27-linked polyubiquitination of PTEN to suppress its dimerization, membrane recruitment, and tumor-suppressive functions both in vitro and in vivo.

WWP1 is genetically amplified and frequently overexpressed in multiple cancers, including those of prostate, breast, and liver, which may lead to pleiotropic inactivation of PTEN. We found that WWP1 may be transcriptionally activated by the MYC proto-oncogene and that genetic depletion of Wwp1 in both Myc-driven mouse models of prostate cancer in vivo and cancer cells in vitro reactivates PTEN function, leading to inhibition of the PI3K-AKT pathway and MYC-driven tumorigenesis. Depletion of Wwp1 significantly reduced PI3K-AKT activity in mouse fibroblasts harboring monoallelic PTEN or PTEN mutations, as observed in PHTS patients. These findings demonstrate that WWP1 acts downstream of MYC and that perturbation of WWP1 is sufficient to restore PTEN tumor-suppressive activity.

We next identified indole-3-carbinol (I3C), a derivative of cruciferous vegetables, as a natural and potent WWP1 inhibitor through structure simulation and biochemical analyses. Pharmacological inactivation of WWP1 by I3C in either Myc-driven or Pten heterozygous mice reactivates PTEN, leading to potent suppression of tumorigenesis driven by the PI3K-AKT pathway. Therefore, genetic or pharmacological targeting of the WWP1-PTEN axis holds promise for patients affected by a number of cancers and other disorders associated with germline mutations of the PTEN gene.

CONCLUSION

We have identified the MYC-WWP1 axis as a fundamental and evolutionary conserved regulatory pathway for PTEN and PI3K signaling. This pathway emerges not only as a rheostat for growth control in physiological conditions but also as a critical vulnerability hijacked for neoplastic transformation, which may be reversed by WWP1 pharmacological inactivation. These findings pave the way toward a long-sought tumor suppressor “reactivation” approach to cancer treatment. Because an increased expression level of MYC-WWP1 or PTEN impairment is widely pervasive in various human cancers, targeting this pathway toward PTEN reactivation may represent an “Achilles heel” of broad application.

Model for WWP1-mediated PTEN K27-linked polyubiquitination in tumor development and progression.

Deregulated MYC overexpression or MYC amplification promotes WWP1 expression and, in turn, triggers PTEN K27-linked polyubiquitination. Aberrant K27-linked polyubiquitination suppresses PTEN dimerization, plasma membrane recruitment, and tumor suppressive function, leading to tumor initiation and progression. Pharmacological inactivation of WWP1 by I3C, a derivative of cruciferous vegetables, reactivates PTEN, leading to suppression of tumorigenesis. PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol 3,4,5-trisphosphate; u, ubiquitin.



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