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Inhibition of Dickkopf-1 enhances the anti-tumor efficacy of sorafenib via inhibition of the PI3K/Akt and Wnt/β-catenin pathways in hepatocellular carcinoma

Authors
 Sang Hyun Seo  ;  Kyung Joo Cho  ;  Hye Jung Park  ;  Hye Won Lee  ;  Beom Kyung Kim  ;  Jun Yong Park  ;  Do Young Kim  ;  Sang Hoon Ahn  ;  Jae Hee Cheon  ;  Jong In Yook  ;  Man-Deuk Kim  ;  Dong Jin Joo  ;  Seung Up Kim 
Citation
 CELL COMMUNICATION AND SIGNALING, Vol.21(1) : 339, 2023-11 
Journal Title
CELL COMMUNICATION AND SIGNALING
Issue Date
2023-11
MeSH
Animals ; Carcinoma, Hepatocellular* / genetics ; Cell Line, Tumor ; Cell Proliferation ; Glycogen Synthase Kinase 3 beta ; Humans ; Liver Neoplasms* / metabolism ; Mice ; Phosphatidylinositol 3-Kinases / metabolism ; Proto-Oncogene Proteins c-akt / metabolism ; Sorafenib / pharmacology ; beta Catenin / metabolism
Keywords
Dickkopf-1 ; GSK3β ; Hepatocellular carcinoma ; Phosphatidylinositol-3-kinase/protein kinase B pathway ; Sorafenib ; Wnt/β-catenin pathway
Abstract
Background: Sorafenib improves the overall survival in patients with advanced hepatocellular carcinoma (HCC). Dickkopf-1 (DKK1) is commonly overexpressed in HCC. In this study, we investigated whether the inhibition of DKK1 enhances the anti-tumor efficacy of sorafenib in HCC.

Methods: HCC cells were treated with sorafenib and WAY-262611, which is an inhibitor of DKK1. Transgenic mouse models were also developed using hydrodynamic tail vein injection. Mice were orally administered with sorafenib (32 mg/kg), WAY-262611 (16 mg/kg), or sorafenib + WAY-262611 for 10 days. Mechanisms of sorafenib and WAY-262611 were explored via western blotting, immunostaining, and RNA sequencing.

Results: DKK1 was significantly overexpressed in patients with HCC than in the healthy controls and patients with liver diseases except HCC (all P < 0.05). Compared with sorafenib alone, sorafenib + WAY-262611 significantly inhibited the cell viability, invasion, migration, and colony formation by promoting apoptosis and altering the cell cycles in HCC cells (all P < 0.05). Moreover, sorafenib + WAY-262611 decreased the p110α, phospho-Akt (all P < 0.05), active β-catenin (all P < 0.05) and phospho-GSK-3β (Ser9) expression levels, while increasing the phospho-GSK-3β (Tyr216) expression levels compared with those in the sorafenib alone in vitro and in vivo. In addition, sorafenib + WAY-262611 inhibited tumor progression by regulating cell proliferation and apoptosis, significantly better than sorafenib alone in mouse models.

Conclusions: Our results indicate that DKK1 inhibition significantly enhances the anti-tumor efficacy of sorafenib by inhibiting the PI3K/Akt and Wnt/β-catenin pathways via regulation of GSK3β activity, suggesting a novel therapeutic strategy for HCC. Video Abstract.
Files in This Item:
T202306716.pdf Download
DOI
10.1186/s12964-023-01355-2
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Radiology (영상의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
2. College of Dentistry (치과대학) > Dept. of Oral Pathology (구강병리학교실) > 1. Journal Papers
Yonsei Authors
Kim, Do Young(김도영)
Kim, Man Deuk(김만득) ORCID logo https://orcid.org/0000-0002-3575-5847
Kim, Beom Kyung(김범경) ORCID logo https://orcid.org/0000-0002-5363-2496
Kim, Seung Up(김승업) ORCID logo https://orcid.org/0000-0002-9658-8050
Park, Jun Yong(박준용) ORCID logo https://orcid.org/0000-0001-6324-2224
Park, Hye Jung(박혜정) ORCID logo https://orcid.org/0000-0002-1862-1003
Ahn, Sang Hoon(안상훈) ORCID logo https://orcid.org/0000-0002-3629-4624
Yook, Jong In(육종인) ORCID logo https://orcid.org/0000-0002-7318-6112
Lee, Hye Won(이혜원) ORCID logo https://orcid.org/0000-0002-3552-3560
Joo, Dong Jin(주동진) ORCID logo https://orcid.org/0000-0001-8405-1531
Cheon, Jae Hee(천재희) ORCID logo https://orcid.org/0000-0002-2282-8904
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/197269
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