Metformin and niclosamide synergistically suppress wnt and yap in apc-mutated colorectal cancer

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

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)

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.

Original languageEnglish
Article number3437
JournalCancers
Volume13
Issue number14
DOIs
Publication statusPublished - 2021 Jul 2

Bibliographical note

Funding Information:
This work was supported by grants from the National Research Foundation of Korea (NRF-2017M3A9G2074773, NRF-2017R1A2B3002241, NRF-2018M3A9E2022820, NRF-2019R1A2C2084535, and NRF-2021R1A2C3003496) funded by the Korea government (MSIP).We thank E. Tunkle for the preparation of the manuscript and K.Y. Kim for the statistical analysis.

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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