Acyl-CoA synthetase VL3 knockdown inhibits human glioma cell proliferation and tumorigenicity.
Acyl-CoA synthetase VL3 knockdown inhibits human glioma cell proliferation and tumorigenicity.
复制标题
DOI：
10.1158/0008-5472.can-08-4689
复制
发表时间：
2009-12-15
期刊：
影响因子：
11.2
通讯作者：
Watkins PA
中科院分区：
文献类型：
--
作者：
Pei Z;Sun P;Huang P;Lal B;Laterra J;Watkins PA
脂质代谢途径对恶性肿瘤的贡献知之甚少。脂肪酰辅酶A合成酶ACSVL3的表达在临床恶性胶质瘤标本中显著升高，但在正常胶质细胞中几乎检测不到。ACSVL3水平与人胶质瘤细胞系和作为异种移植物繁殖的胶质瘤细胞的恶性行为相关。ACSVL3表达由致癌受体酪氨酸激酶（RTK）c-Met和EGFR的激活诱导。用中和性抗HGF单克隆抗体抑制c-Met活化可降低ACSVL3表达，同时在体内抑制肿瘤生长。使用RNA干扰敲低ACSVL3表达，降低长链脂肪酸活化，分别抑制锚定依赖性和锚定非依赖性胶质瘤细胞生长约70%和约90%。ACSVL3耗尽的细胞的致瘤性低于对照细胞，并且皮下异种移植物的生长比对照肿瘤慢约60%。由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 - 86%。ACSVL 3敲除会破坏Akt的功能，这一点可以通过半胱氨酸蛋白酶依赖性机制通过RTK诱导总Akt和磷酸化Akt以及GSK 3 β的短暂减少来证明。表达组成型活性myr-Akt将细胞从ACSVL3耗竭的锚定依赖性和锚定非依赖性生长抑制作用中拯救出来。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胶质瘤细胞的致癌特性。
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 EGFR. Inhibiting c-Met activation with neutralizing anti-HGF 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 ~70% and ~ 90%, respectively. ACSVL3-depleted cells were less tumorigenic than control cells and subcutaneous xenografts grew ~60% slower than control tumors. Orthotopic xenografts produced by ACSVL3-depleted cells were 82–86 % smaller than control xenografts. ACSVL3 knockdown disrupted Akt function as evidenced by RTK-induced transient decreases in total and phosphorylated Akt, as well as GSK3β, 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.