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.