2. Academic Validation
  3. Nucleos(t)ide analogs for hepatitis B virus infection differentially regulate the growth factor signaling in hepatocytes

Nucleos(t)ide analogs for hepatitis B virus infection differentially regulate the growth factor signaling in hepatocytes

  • Hepatol Commun. 2024 Jan 5;8(1):e0351. doi: 10.1097/HC9.0000000000000351.
Ryogo Shimizu 1,  Kazuhisa Murai 1,  Kensuke Tanaka 1,  Yuga Sato 1,  Naho Takeda 1,  Saki Nakasyo 1,  Takayoshi Shirasaki 1,  Kazunori Kawaguchi 2,  Tetsuro Shimakami 2,  Kouki Nio 2,  Yuki Nakaya 3,  Harumi Kagiwada 4,  Katsuhisa Horimoto 5,  Masashi Mizokami 6,  Shuichi Kaneko 2,  Kazumoto Murata 3 6,  Taro Yamashita 2,  Masao Honda 1 2
Affiliations

Affiliations

  • 1 Department of Clinical Laboratory Medicine, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.
  • 2 Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
  • 3 Department of Infection and Immunity, Division of Virology, Jichi Medical University, Shimotsuke, Japan.
  • 4 Biological Data Science Research Group, Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology, Tokyo, Japan.
  • 5 Artificial Intelligence Research Center, National Institute of Advanced Industrial Science and Technology, Tokyo, Japan.
  • 6 Genome Medical Sciences Project, National Center for Global Health and Medicine, Ichikawa, Japan.
PMID: 38180972 DOI: 10.1097/HC9.0000000000000351
Abstract

Background: Recent clinical studies have suggested that the risk of developing HCC might be lower in patients with chronic hepatitis B receiving tenofovir disoproxil fumarate than in patients receiving entecavir, although there is no difference in biochemical and virological remission between the 2 drugs.

Methods: The effects of nucleoside analogs (NsAs; lamivudine and entecavir) or nucleotide analogs (NtAs; adefovir disoproxil, tenofovir disoproxil fumarate, and tenofovir alafenamide) on cell growth and the expression of growth signaling molecules in hepatoma cell lines and PXB cells were investigated in vitro. The tumor inhibitory effects of NsAs or NtAs were evaluated using a mouse xenograft model, and protein phosphorylation profiles were investigated. The binding of NsAs or NtAs to the Insulin Receptor (INSR) was investigated by thermal shift assays.

Results: NtAs, but not NsAs, showed direct growth inhibitory effects on hepatoma cell lines in vitro and a mouse model in vivo. A phosphoprotein array revealed that INSR signaling was impaired and the levels of phosphorylated (p)-INSRβ and downstream molecules phosphorylated (p)-IRS1, p-AKT, p-Gab1, and p-SHP2 were substantially reduced by NtAs. In addition, p-epidermal growth factor receptor and p-AKT levels were substantially reduced by NtAs. Similar findings were also found in PXB cells and nontumor lesions of liver tissues from patients with chronic hepatitis B. Prodrug NtAs, but not their metabolites (adefovir, adefovir monophosphate, adefovir diphosphate, tenofovir, tenofovir monophosphate, and tenofovir diphosphate), had such effects. A thermal shift assay showed the binding of NtAs to INSRβ.

Conclusions: NtAs (adefovir disoproxil, tenofovir disoproxil fumarate, and tenofovir alafenamide), which are adenine derivative acyclic nucleotide analogs, potentially bind to the ATP-binding site of growth factor receptors and inhibit their autophosphorylation, which might reduce the risk of HCC in patients with chronic hepatitis B.

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