S-棕榈酰化修饰的 PCSK9 通过激活 PI3K/AKT 通路诱导肝癌产生索拉非尼耐药性。
S-palmitoylation of PCSK9 induces sorafenib resistance in liver cancer by activating the PI3K/AKT pathway.
机构信息
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 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.
出版信息
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.
索拉非尼是目前治疗晚期肝细胞癌（HCC）的一线药物。然而，索拉非尼耐药仍然是一个重大挑战。AKT 信号通路的异常激活是导致 HCC 索拉非尼耐药的重要机制。蛋白水解酶原转化酶枯草杆菌蛋白酶/kexin 9（PCSK9）在抗肿瘤免疫反应中起着至关重要的作用。在这项研究中，我们证明异常的 PCSK9 上调通过诱导 AKT-S473 磷酸化促进 HCC 细胞增殖和索拉非尼耐药。在半胱氨酸 600 发生棕榈酰化后，PCSK9 与张力蛋白同源物（PTEN）的结合亲和力大大增加，导致溶酶体介导的 PTEN 降解和随后的 AKT 激活。我们确定锌指 DHHC 型棕榈酰转移酶 16（ZDHHC16）是一种促进 PCSK9 半胱氨酸 600 棕榈酰化的棕榈酰转移酶。我们还开发了一种具有生物活性的 PCSK9 衍生肽，它可竞争性抑制 PCSK9 棕榈酰化，抑制 AKT 磷酸化，并增强 HCC 中索拉非尼的抗肿瘤作用。
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