2. Academic Validation
  3. S-palmitoylation of PCSK9 induces sorafenib resistance in liver cancer by activating the PI3K/AKT pathway

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.
Yan Sun 1,  Huan Zhang 1,  Junpeng Meng 2,  Feng Guo 1,  Dianyun Ren 3,  Heshui Wu 4,  Xin Jin 5
Affiliations

Affiliations

  • 1 Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
  • 2 Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Department of General Surgery, the Second Hospital of Shanxi Medical University, Taiyuan, 030001 Shanxi, China.
  • 3 Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Electronic address: rendianyun@hust.edu.cn.
  • 4 Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Electronic address: heshuiwu@hust.edu.cn.
  • 5 Department of Urology, the Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; Uro-Oncology Institute of Central South University, Changsha, Hunan 410011, China. Electronic address: jinxinxy2@csu.edu.cn.
PMID: 35977495 DOI: 10.1016/j.celrep.2022.111194
Abstract

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.

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