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]

Recent experiments have shown that hydrogels with enhanced toughness can be synthesized by incorporating self-healing physical cross-links in a chemically cross-linked gel network. These gels exhibit rate dependent mechanical behavior, suggesting that improved mechanical properties are closely tied to the breaking and reattaching of temporary crosslinks in the gel network. In this work, the connection between rate dependent mechanical behavior and kinetics of breaking and reattachment of temporary cross-links is quantified using a three-dimensional finite strain constitutive model. The parameters of the model are fitted using relaxation and constant strain rate tests in uniaxial tension of a model dualcross-link gel. The stress versus time curves of more complex strain histories, involving loading followed by unloading at different rates, is successfully and quantitatively predicted by our model. Such modeling strategy combining physically based kinetics and three-dimensional large strain mechanics shows great promise for quantitative modeling of soft biological tissues and synthetic counterparts containing dynamic bonds.