S-palmitoylation of PCSK9 induces sorafenib resistance in liver cancer by activating the PI3K/AKT pathway
| Autor: | Yan Sun, Huan Zhang, Junpeng Meng, Feng Guo, Dianyun Ren, Heshui Wu, Xin Jin |
|---|---|
| Rok vydání: | 2022 |
| Předmět: |
Niacinamide
Carcinoma Hepatocellular Lipoylation Phenylurea Compounds Liver Neoplasms Hep G2 Cells Sorafenib General Biochemistry Genetics and Molecular Biology Phosphatidylinositol 3-Kinases Drug Resistance Neoplasm Cell Line Tumor Humans Cysteine Proprotein Convertase 9 Proto-Oncogene Proteins c-akt |
| Zdroj: | Cell reports. 40(7) |
| ISSN: | 2211-1247 |
| Popis: | Sorafenib is currently the first-line treatment for advanced hepatocellular carcinoma (HCC). However, sorafenib resistance remains a significant challenge. Aberrant AKT signaling activation is a crucial mechanism driving sorafenib resistance in HCC. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a vital role in antitumor immune responses. In this study, we demonstrate that aberrant PCSK9 upregulation promotes cell proliferation and sorafenib resistance in HCC by inducing AKT-S473 phosphorylation. After palmitoylation at cysteine 600, the binding affinity between PCSK9 and tensin homolog (PTEN) is dramatically increased, inducing lysosome-mediated PTEN degradation and subsequent AKT activation. We identify zinc finger DHHC-type palmitoyltransferase 16 (ZDHHC16) as a palmitoyltransferase that promotes PCSK9 palmitoylation at cysteine 600. We also develop a biologically active PCSK9-derived peptide that competitively inhibits PCSK9 palmitoylation, suppressing AKT phosphorylation and augmenting the antitumor effects of sorafenib in HCC. |
| Databáze: | OpenAIRE |
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