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

Yan Sun; Huan Zhang; Junpeng Meng; Feng Guo; Dianyun Ren; Heshui Wu; Xin Jin

doi:10.1016/j.celrep.2022.111194

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.

Authors

Yan Sun¹, Huan Zhang¹, Junpeng Meng², Feng Guo¹, Dianyun Ren³, Heshui Wu⁴, Xin Jin⁵

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.

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

Substances

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