Hugo W. Moser Research Institute at Kennedy Krieger and Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Cancer Res. 2009 Dec 15;69(24):9175-82. doi: 10.1158/0008-5472.CAN-08-4689.
The contribution of lipid metabolic pathways to malignancy is poorly understood. Expression of the fatty acyl-CoA synthetase ACSVL3 was found to be markedly elevated in clinical malignant glioma specimens but nearly undetectable in normal glia. ACSVL3 levels correlated with the malignant behavior of human glioma cell lines and glioma cells propagated as xenografts. ACSVL3 expression was induced by the activation of oncogenic receptor tyrosine kinases (RTK) c-Met and epidermal growth factor receptor. Inhibiting c-Met activation with neutralizing anti-hepatocyte growth factor monoclonal antibodies reduced ACSVL3 expression concurrent with tumor growth inhibition in vivo. ACSVL3 expression knockdown using RNA interference, which decreased long-chain fatty acid activation, inhibited anchorage-dependent and anchorage-independent glioma cell growth by approximately 70% and approximately 90%, respectively. ACSVL3-depleted cells were less tumorigenic than control cells, and subcutaneous xenografts grew approximately 60% slower than control tumors. Orthotopic xenografts produced by ACSVL3-depleted cells were 82% to 86% smaller than control xenografts. ACSVL3 knockdown disrupted Akt function as evidenced by RTK-induced transient decreases in total and phosphorylated Akt, as well as glycogen synthase kinase 3beta, via a caspase-dependent mechanism. Expressing constitutively active myr-Akt rescued cells from the anchorage-dependent and anchorage-independent growth inhibitory effects of ACSVL3 depletion. These studies show that ACSVL3 maintains oncogenic properties of malignant glioma cells via a mechanism that involves, in part, the regulation of Akt function.
脂质代谢途径对恶性肿瘤的作用知之甚少。研究发现，酰基辅酶 A 合成酶 ACSVL3 在临床恶性脑胶质瘤标本中表达明显升高，而在正常神经胶质中几乎检测不到。ACSVL3 水平与人类神经胶质瘤细胞系和作为异种移植物增殖的神经胶质瘤细胞的恶性行为相关。ACSVL3 的表达受致癌受体酪氨酸激酶 (RTK) c-Met 和表皮生长因子受体的激活诱导。用中和抗肝细胞生长因子单克隆抗体抑制 c-Met 激活，可降低 ACSVL3 的表达，同时抑制体内肿瘤生长。使用 RNA 干扰降低 ACSVL3 表达，减少长链脂肪酸激活，可使锚定依赖性和非锚定依赖性神经胶质瘤细胞生长分别减少约 70%和 90%。与对照细胞相比，ACSVL3 耗尽的细胞致瘤性降低，皮下异种移植物的生长速度比对照肿瘤慢约 60%。ACSVL3 耗尽的细胞产生的原位异种移植物比对照异种移植物小 82%至 86%。ACSVL3 敲低通过 caspase 依赖性机制破坏 Akt 功能，表现为 RTK 诱导的总和磷酸化 Akt 以及糖原合酶激酶 3β的短暂减少。表达组成型激活的 myr-Akt 可挽救细胞免受 ACSVL3 耗竭对锚定依赖性和非锚定依赖性生长抑制作用的影响。这些研究表明，ACSVL3 通过部分涉及 Akt 功能调节的机制维持恶性脑胶质瘤细胞的致癌特性。
