Enhanced glucose and lipid metabolism is one of the most common properties of malignant cells. ATP citrate lyase (ACLY) is a key enzyme of de novo fatty acid synthesis responsible for generating cytosolic acetyl-CoA and oxaloacetate. To evaluate its role in lung cancer progression, we here analyzed ACLY expression in a subset of human lung adenocarcinoma cell lines and showed a relationship with the phosphatidyl-inositol-3 kinase-Akt pathway. The introduction of constitutively active Akt into cells enhanced the phosphorylation of ACLY, whereas dominant-negative Akt caused attenuation. In human lung adenocarcinoma samples, ACLY activity was found to be significantly higher than in normal lung tissue. Immunohistochemical analysis further showed phosphorylated ACLY overexpression in 162 tumors, well-correlating with stage, differentiation grade, and a poorer prognosis. Finally, to show the therapeutic potential and mechanism of ACLY inhibition for lung cancer treatment, we assessed the effect of RNA interference targeting ACLY on lipogenesis and cell proliferation in A549 cells. ACLY inhibition resulted in growth arrest in vitro and in vivo. Interestingly, increased intracellular lipids were found in ACLY knockdown cells, whereas de novo lipogenesis was inhibited. Supplementation of insulin could rescue the proliferative arrest elicited by ACLY inhibition; however, in contrast, fatty acid palmitate induced cell death. Taken together, these findings suggest that ACLY is involved in lung cancer pathogenesis associated with metabolic abnormality and might offer a novel therapeutic target. [Cancer Res 2008;68(20):8547-54]

Immunohistochemical examination of ER-beta1 in addition to ER-alpha and PR is clinically important in patients with breast cancer treated with tamoxifen monotherapy. Further studies are needed to confirm our findings.

The hypothesis that bioactive glass particulate increases the rate of bone proliferation over that of synthetic hydroxyapatite and bioactive glass-ceramic was tested in these experiments. Three types of bioactive particles-45S5 Bioglass(R), synthetic hydroxyapatite, and A-W glass-ceramic-were implanted in 6-mm-diameter holes drilled in the femoral condyles of mature rabbits. Bone growth rate was measured using an image processor. 45S5 Bioglass(R) produced bone more rapidly than either A-W glass-ceramic or hydroxyapatite. At the later time periods, 45S5 Bioglass(R) was resorbed more quickly than A-W glass-ceramic. Synthetic hydroxyapatite was not resorbed at all. Backscattered electron imaging suggested that the resorption process occurred by solution-mediated dissolution, which produced chemical changes in the enclosed particulate. It was concluded that the rate of bone growth correlates with the rate of dissolution of silica as the particles resorb.

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