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 language | English |
|---|---|
| Article number | 3437 |
| Journal | Cancers |
| Volume | 13 |
| Issue number | 14 |
| DOIs | |
| Publication status | Published - 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
