丁香酚通过靶向β-catenin（一种肺癌致癌作用中的中央癌症干细胞调节剂）而成为长生不老药：体内和体外原理,Food & Function

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丁香酚通过靶向β-catenin（一种肺癌致癌作用中的中央癌症干细胞调节剂）而成为长生不老药：体内和体外原理
Food & Function ( IF 5.1 ) Pub Date : 2020-12-22 , DOI: 10.1039/d0fo02105a
Pritha Choudhury _{1,

2,

3,

4} , Atish Barua _{1,

2,

3,

4} , Anup Roy _{4,

5,

6,

7} , Rudradip Pattanayak _{8,

9,

10,

11,

12} , Maitree Bhattacharyya _{4,

13,

14,

15} , Prosenjit Saha _{1,

2,

3,

4}

Affiliation

根据基于人群的研究，肺癌已成为全球男性死亡的主要原因之一，并且女性死亡率正以惊人的速度上升。这项研究的目的是利用丁香酚的固有特性来限制烟草相关的人类致癌物NDEA诱导的体内肺癌致癌模型中癌细胞的生长作为化学预防剂。更确切地说，丁香酚（丁香酚的一种成分）通过利用其自然界中的丰富成分，以经济有效的方式在NDEA诱导的小鼠肺癌发生模型中建立化学预防的分子机制，并在A549人肺中得到验证癌细胞系。我们的研究特别针对癌细胞（称为CSC）的微小，抗药性和最具毒性的亚群，方法是靶向其调节分子β-catenin。丁子香酚的无毒剂量可增强细胞凋亡，同时抑制致癌物治疗小鼠的肺组织中的细胞增殖，而不会影响正常小鼠。丁子香酚结合细胞凋亡和增殖，在这种肺癌发生模型中显示出卓越的化学预防潜力。重要的，丁香酚作为化学预防剂强烈限制了处于轻度增生阶段的肺癌。分子分析显着描述了β-catenin核转运的限制。丁子香酚处理后最小的总β-catenin库和诱导的N末端Ser37磷酸化形式导致其胞质降解。因此，ISC，ICC和WB分析均证明，其表达依赖于β-catenin的CSC标记（例如CD44，Oct4，EpCAM和Notcht1）显着下降。体内和体外。在体外次级球形成测定也证明了显着抑制CSC群体，并且因此毒力。换句话说，当通过CK1α抑制剂D4476在体外通过Western blot处理时，丁子香酚被证明可显着增强β-catenin的降解。Wnt /β-catenin途径中的CK1α在标记β-catenin的N端Ser45磷酸化中起关键作用，这最终为GSK3β在Ser37残基发生决定性的磷酸化打开了一个位置。因此，CSC的最终灭绝与治疗失败导致的复发有关。这可以以自然，经济的方式帮助实现更长和更好的生活质量。

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Eugenol emerges as an elixir by targeting β-catenin, the central cancer stem cell regulator in lung carcinogenesis: an in vivo and in vitro rationale

According to population-based studies, lung cancer has become one of the leading causes of death globally in males and is also rising in females at an alarming rate. The aim of this study was to exploit the inherent properties of eugenol to restrict the growth of cancer cells in a tobacco-related human carcinogen NDEA-induced lung carcinogenesis model in vivo as a chemopreventive agent. More precisely, by utilizing its abundance in nature, eugenol (a component of clove) was utilized to establish the molecular mechanism of chemoprevention in the NDEA-induced mouse lung carcinogenesis model in a substantial cost-effective manner and was validated in the A549 human lung cancer cell line. Our study especially targeted the tiny, drug-resistant, and most virulent subpopulation of cancer cells called CSCs by targeting their regulator molecule β-catenin. The non-toxic dosage of eugenol was shown to enhance apoptosis, simultaneously suppressing cell proliferation in the lung tissue of carcinogen-treated mice without affecting the normal mice. Combining cellular apoptosis and proliferation, eugenol showed an exceptional chemopreventive potential in this lung carcinogenesis model. Importantly, eugenol strongly restricted the lung carcinoma in the mild dysplastic stage as a chemopreventive agent. The molecular analysis remarkably depicted the restriction of β-catenin nuclear transportation. The minimized total β-catenin pool and induced N-terminal Ser37 phosphorylation form after eugenol treatment resulted in its cytoplasmic degradation. Consequently, CSC markers such as CD44, Oct4, EpCAM, and Notcht1, whose expression is dependent on β-catenin decreased significantly, as proven by IHC, ICC, and WB analysis both in vivo and in vitro. The in vitro secondary sphere formation assay also proved the remarkably repressed CSC population, and hence the virulence. In another way, eugenol was proven to significantly enhance the degradation of β-catenin when treated with the CK1α inhibitor D4476 in vitro by Western blot. CK1α in the Wnt/β-catenin pathway plays a crucial role for tagging with the N-terminal Ser45 phosphorylation of β-catenin, which ultimately opens a position for the decisive phosphorylation by GSK3β at the Ser37 residue to take place. Thus, the conclusive extermination of CSCs achieved that was associated with recurrence due to treatment failure. That can help to achieve a longer and better quality of life in a natural, economical way.

更新日期：2021-01-15

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