Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, Maryland, United States of America.
PLoS One. 2013 Jul 23;8(7):e69392. doi: 10.1371/journal.pone.0069392. Print 2013.
Lung cancer is the leading cause of cancer deaths worldwide. In the United States, only one in six lung cancer patients survives five years after diagnosis. These statistics may improve if new therapeutic targets are identified. We previously reported that an enzyme of fatty acid metabolism, very long-chain acyl-CoA synthetase 3 (ACSVL3), is overexpressed in malignant glioma, and that depleting glioblastoma cells of ACSVL3 diminishes their malignant properties. To determine whether ACSVL3 expression was also increased in lung cancer, we studied tumor histologic sections and lung cancer cell lines. Immunohistochemical analysis of normal human lung showed moderate ACSVL3 expression only in bronchial epithelial cells. In contrast, all of 69 different lung tumors tested, including adeno-, squamous cell, large cell, and small cell carcinomas, had robustly elevated ACSVL3 levels. Western blot analysis of lung cancer cell lines derived from these tumor types also had significantly increased ACSVL3 protein compared to normal bronchial epithelial cells. Decreasing the growth rate of lung cancer cell lines did not change ACSVL3 expression. However, knocking down ACSVL3 expression by RNA interference reduced cell growth rates in culture by 65-76%, and the ability of tumor cells to form colonies in soft agar suspension by 65-80%. We also conducted studies to gain a better understanding of the biochemical properties of human ACSVL3. ACSVL3 mRNA was detected in many human tissues, but the expression pattern differed somewhat from that of the mouse. The enzyme activated long- and very long-chain saturated fatty acid substrates, as well as long-chain mono- and polyunsaturated fatty acids to their respective coenzyme A derivatives. Endogenous human ACSVL3 protein was found in a punctate subcellular compartment that partially colocalized with mitochondria as determined by immunofluorescence microscopy and subcellular fractionation. From these studies, we conclude that ACSVL3 is a promising new therapeutic target in lung cancer.
肺癌是全球癌症死亡的主要原因。在美国，只有六分之一的肺癌患者在诊断后五年内存活。如果能确定新的治疗靶点，这些数据可能会有所改善。我们之前报道过，脂肪酸代谢酶——长链酰基辅酶 A 合成酶 3（ACSVL3）在恶性神经胶质瘤中过度表达，耗尽神经胶质瘤细胞中的 ACSVL3 会降低其恶性特性。为了确定肺癌中是否也增加了 ACSVL3 的表达，我们研究了肿瘤组织学切片和肺癌细胞系。对正常人类肺的免疫组织化学分析显示，支气管上皮细胞中只有中等水平的 ACSVL3 表达。相比之下，我们测试的 69 种不同的肺癌肿瘤中，包括腺癌、鳞状细胞癌、大细胞癌和小细胞癌，均有明显升高的 ACSVL3 水平。这些肿瘤类型衍生的肺癌细胞系的 Western blot 分析也显示，与正常支气管上皮细胞相比，ACSVL3 蛋白水平显著增加。降低肺癌细胞系的生长速度并不能改变 ACSVL3 的表达。然而，通过 RNA 干扰敲低 ACSVL3 表达会使细胞在培养中的生长速度降低 65-76%，并使肿瘤细胞在软琼脂悬浮液中形成集落的能力降低 65-80%。我们还进行了研究，以更好地了解人类 ACSVL3 的生化特性。ACSVL3 mRNA 在许多人体组织中均有检测到，但表达模式与小鼠略有不同。该酶激活长链和超长链饱和脂肪酸底物，以及长链单不饱和和多不饱和脂肪酸，形成相应的辅酶 A 衍生物。通过免疫荧光显微镜和亚细胞分级分离，发现内源性人类 ACSVL3 蛋白位于点状亚细胞区室中，部分与线粒体共定位。从这些研究中，我们得出结论，ACSVL3 是肺癌治疗的一个很有前途的新靶点。
