C24-Ceramide Drives Gallbladder Cancer Progression through Directly Targeting PIP4K2C to Facilitate mTOR Signaling Activation
C24-Ceramide Drives Gallbladder Cancer Progression through Directly Targeting PIP4K2C to Facilitate mTOR Signaling Activation
复制标题
C24-神经酰胺通过直接靶向 PIP4K2C 促进 mTOR 信号激活来驱动胆囊癌进展
作者：
Zhang Yonglong;Wang Hui;Chen Tao;Wang Haolu;Liang Xiaowen;Zhang Yuchen;Duan Jinlin;Qian Shenjiao;Qiao Ke;Zhang Lei;Liu Yanfeng;Wang Jian
背景和目的胆囊癌（GBC）化疗耐药的广泛流行和早期诊断的不完善导致患者预后不良，需要持续努力寻找有效的生物标志物和治疗干预。神经酰胺已成为与肿瘤发生和癌症治疗反应相关的细胞内信号分子。然而，神经酰胺与GBC的临床相关性尚未研究。方法和结果在本研究中，我们揭示了异常的基因表达（例如，丝氨酸棕榈酰转移酶1 [SPTLC 1]和神经酰胺合成酶2 [CERS 2]）在GBC组织中促进新生神经酰胺生物合成和长度特异性神经酰胺的产生。对健康对照、胆囊结石和GBC患者血清神经酰胺模式的分析表明，C24-神经酰胺是GBC患者的潜在诊断生物标志物。重要的是，SPTLC 1、CERS 2及其产物C24-神经酰胺的升高与肿瘤分期、远端转移和预后不良相关。与此一致，C24-神经酰胺在体外和体内促进GBC细胞增殖和迁移。从机制上讲，C24-神经酰胺直接结合到磷脂酰肌醇5-磷酸4-激酶2型γ（PIP 4K 2C），一种哺乳动物雷帕霉素靶蛋白（mTOR）的调节剂，以促进mTOR复合物的形成和激活。C6-神经酰胺（天然神经酰胺的类似物）与C24-神经酰胺竞争PIP 4K 2C结合，从而消除C24-神经酰胺介导的mTOR信号激活和致癌活性。C6-神经酰胺可显著抑制GBC细胞的增殖和转移能力，这一作用依赖于PIP4K2C.ConclusionsOur发现突出了神经酰胺代谢与GBC进展的临床相关性，并确定C24-神经酰胺作为GBC的诊断生物标志物。我们认为PIP 4K 2C是C6-神经酰胺不可或缺的，通过与C24-神经酰胺的直接竞争，作为GBC的潜在治疗干预。
Background and AimsThe wide prevalence of chemoresistance and compromised early diagnosis of gallbladder cancer (GBC) has led to poor patient prognosis, requiring sustained efforts for the identification of effective biomarkers and therapeutic intervention. Ceramides have emerged as intracellular signaling molecules linked to tumorigenesis and therapeutic response in cancers. However, the clinical relevance of ceramides with GBC has not been investigated.Approach and ResultsIn the present study, we revealed aberrant gene expressions (e.g., serine palmitoyltransferase 1 [SPTLC1] and ceramide synthase 2 [CERS2]) ofde novoceramide biosynthesis and length‐specific ceramide production in GBC tissues. Analyses of serum ceramide pattern in healthy controls, gallbladder stone, and GBC patients identified C24‐Ceramide as a potential diagnostic biomarker for patients with GBC. Importantly, elevation of SPTLC1, CERS2, and its product, C24‐Ceramide, was associated with tumor staging, distal metastasis, and worse prognosis. In line with this, C24‐Ceramide promoted GBC cell proliferation and migrationin vitroandin vivo. Mechanistically, C24‐Ceramide directly bound to phosphatidylinositol 5‐phosphate 4‐kinase type‐2 gamma (PIP4K2C), a regulator of mammalian target of rapamycin (mTOR), to facilitate mTOR complex formation and activation. C6‐Ceramide, an analogue of natural ceramide, competed with C24‐Ceramide for PIP4K2C binding, thereby abrogating C24‐Ceramide–mediated mTOR signaling activation and oncogenic activity. Furthermore, stimulation with C6‐Ceramide significantly suppressed the proliferative and metastatic capacity of GBC cellsin vitroandin vivo, which was dependent on PIP4K2C.ConclusionsOur findings highlight the clinical relevance of ceramide metabolism with GBC progression and identify C24‐Ceramide as a diagnostic biomarker for GBC. We propose that PIP4K2C is indispensable for C6‐Ceramide as a potential therapeutic intervention for GBC through a direct competition with C24‐Ceramide.