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二甲双胍和氯硝柳胺协同抑制APC突变型结直肠癌中的Wnt和YAP信号通路

Metformin and Niclosamide Synergistically Suppress Wnt and YAP in APC-Mutated Colorectal Cancer.

作者信息

Kang Hee Eun, Seo Yoojeong, Yun Jun Seop, Song Sang Hyun, Han Dawool, Cho Eunae Sandra, Cho Sue Bean, Jeon Yoon, Lee Ho, Kim Hyun Sil, Kang Joyeon, Yook Jong In, Kim Nam Hee, Kim Tae Il

机构信息

Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul 03722, Korea.

Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Korea.

出版信息

Cancers (Basel). 2021 Jul 9;13(14):3437. doi: 10.3390/cancers13143437.

DOI:10.3390/cancers13143437
PMID:34298652
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8308039/
Abstract

The Wnt and Hippo pathways are tightly coordinated and understanding their reciprocal regulation may provide a novel therapeutic strategy for cancer. Anti-helminthic niclosamide is an effective inhibitor of Wnt and is now in a phase II trial for advanced colorectal cancer (CRC) patients. We found that Axin2, an authentic target gene of canonical Wnt, acts as aYAP phosphorylation activator in APC-mutated CRC. While niclosamide effectively suppresses Wnt, it also inhibits Hippo, limiting its therapeutic potential for CRC. To overcome this limitation, we utilized metformin, a clinically available AMPK activator. This combinatory approach not only suppresses canonical Wnt activity, but also inhibits YAP activity in CRC cancer cells and in patient-derived cancer organoid through the suppression of cancer stemness. Further, combinatory oral administration suppressed in vivo tumorigenesis and the cancer progression of APC-MIN mice models. Our observations provide not only a reciprocal link between Wnt and Hippo, but also clinically available novel therapeutics that are able to target Wnt and YAP in APC-mutated CRC.

摘要

Wnt和Hippo信号通路紧密协调，了解它们的相互调节可能为癌症提供一种新的治疗策略。抗蠕虫药物氯硝柳胺是Wnt的有效抑制剂，目前正处于晚期结直肠癌（CRC）患者的II期试验中。我们发现，作为经典Wnt真正靶基因的Axin2在APC突变的CRC中作为YAP磷酸化激活剂发挥作用。虽然氯硝柳胺有效地抑制Wnt，但它也抑制Hippo，限制了其对CRC的治疗潜力。为了克服这一限制，我们使用了二甲双胍，一种临床可用的AMPK激活剂。这种联合方法不仅抑制经典Wnt活性，还通过抑制癌症干性来抑制CRC癌细胞和患者来源的癌症类器官中的YAP活性。此外，联合口服给药抑制了APC-MIN小鼠模型的体内肿瘤发生和癌症进展。我们的观察结果不仅提供了Wnt和Hippo之间的相互联系，还提供了能够靶向APC突变CRC中的Wnt和YAP的临床可用新型疗法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e8e/8308039/d52a3ab97580/cancers-13-03437-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e8e/8308039/292794f6a875/cancers-13-03437-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e8e/8308039/96e68a7f2b38/cancers-13-03437-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e8e/8308039/e97ea150c07c/cancers-13-03437-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e8e/8308039/aa1607145c19/cancers-13-03437-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e8e/8308039/51ee5d62d7d5/cancers-13-03437-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e8e/8308039/d52a3ab97580/cancers-13-03437-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e8e/8308039/292794f6a875/cancers-13-03437-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e8e/8308039/96e68a7f2b38/cancers-13-03437-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e8e/8308039/e97ea150c07c/cancers-13-03437-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e8e/8308039/aa1607145c19/cancers-13-03437-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e8e/8308039/51ee5d62d7d5/cancers-13-03437-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e8e/8308039/d52a3ab97580/cancers-13-03437-g006.jpg

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