S-palmitoylation of PCSK9 induces sorafenib resistance in liver cancer by activating the PI3K/AKT pathway

Cell Rep. 2022 Aug 16;40(7):111194. doi: 10.1016/j.celrep.2022.111194.


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.

Keywords: AKT; CP: Cancer; CP: Molecular biology; PCSK9; PTEN; ZDHHC16; liver cancer; palmitoylation; sorafenib resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Hepatocellular* / pathology
  • Cell Line, Tumor
  • Cysteine / metabolism
  • Drug Resistance, Neoplasm
  • Hep G2 Cells
  • Humans
  • Lipoylation
  • Liver Neoplasms* / pathology
  • Niacinamide / pharmacology
  • Phenylurea Compounds / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proprotein Convertase 9 / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Sorafenib / pharmacology


  • Phenylurea Compounds
  • Niacinamide
  • Sorafenib
  • Proto-Oncogene Proteins c-akt
  • PCSK9 protein, human
  • Proprotein Convertase 9
  • Cysteine