PO.MCB09.02 · 分子与细胞生物学
多硫化物参与FSCN-1的过硫化以加速胰腺导管腺癌的发展
Polysulfides contribute to persulfidation of FSCN-1 to accelerate development of pancreatic ductal adenocarcinoma
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摘要 Abstract
中文摘要
我们此前报道了多硫化物(PS)在卵巢癌和乳腺癌中过度生成,导致预后恶化和化疗耐药(1,2),但分子机制仍不明确。在本研究中,使用来自120例日本患者的FFPE样本,通过免疫组织化学检测了术后胰腺导管腺癌(PDAC)组织中PS生成酶的表达。分析显示,在癌症相关成纤维细胞(CAF)中表达的胱硫醚gamma-裂解酶(CSE)是恶化术后无病生存和总生存的独立因素。CSE阳性CAF主要出现在邻近癌细胞的区域,并激活糖酵解以向转硫途径输送C1单元,这可通过激活丝氨酸-半胱氨酸合成碳输送的PFKFB3和PKM2甲基化升高来判断。使用冷冻PDAC组织进行的基于金纳米颗粒的表面增强拉曼光谱(SERS)成像(3)揭示了癌组织上的PS生成。PS使癌细胞诱导fascin-肌动蛋白束缚蛋白(FSCN)-1的位点特异性过硫化,从而刺激癌细胞的迁移能力,而PS降解剂氨溴索或吉西他滨则通过其在体外清除PS的作用抵消了这些效应。这些结果提示PS作为诱导CAF介导的癌症侵袭性的标志物。参考文献
(1) Yamamoto T, 等。Cancer Res (2024)(2) Honda K, 等。Redox Biol (2021)(3) Shiota M, 等。Nature Commun (2018)
查看英文原文 English abstract
We previously reported polysulfides (PS) are overgenerated in ovarian and breast cancers that contribute to worsening prognosis and chemoresistance (1, 2), while molecular mechanisms remain unknown. In this study, expression of PS-generating enzymes in post-operative pancreatic ductal adenocarcinoma (PDAC) tissues were examined immunohistochemically using FFPE samples from 120 Japanese patients. Analyses revealed that cystathionine gamma-lyase (CSE) expressed in cancer-associated fibroblasts (CAF) serves as an independent factor worsening post-operative disease-free and overall survivals. CSE-positive CAF predominantly occurs in regions adjacent to cancer cells and activated glycolysis to deliver C1 units towards transsulfudation as judged by elevated methylation of PFKFB3 and PKM2 that activates the carbon delivery for serine-cysteine synthesis. Gold nanoparticle-based surface-enhanced Raman spectroscopy (SERS) imaging (3) using frozen PDAC tissues unveiled PS generation over the cancer tissues. PS renders cancer cells to induce site-specific persulfidation of fascin-actin-bundling protein (FSCN)-1 to stimulate the ability of cancer cells to migrate, while PS-degrading ambroxol or gemcitabine canceled the effects through their action to scavenge PS in vitro. These results suggest that PS serves as a marker inducing CAF-mediated cancer invasiveness.References
(1) Yamamoto T, et al. Cancer Res (2024)(2) Honda K, et al. Redox Biol (2021)(3) Shiota M, et al. Nature Commun (2018)
利益披露 Disclosure
M. Suematsu, None..
T. Yamamoto, None..
M. Takizawa, None..
C. Nishime, None..
M. Suzuki, None..
N. Hiraoka, None.