关键词：半胱天冬酶2;细胞(生物学);化疗药物;化疗;死亡;脂肪酸合成;脂肪酸;葡萄糖;代谢;卵巢癌;肽水解酶;扰动;磷酸化
摘 要：Following treatment with chemotherapeutic agents, responsive ovarian cancer cells undergo apoptotic cell death. Several groups have shown that the apoptotic protease, caspase 2 (C2), is an essential activator of cell death in ovarian cancer cells treated with cisplatin and we have found, by knock-down of C2 in ovarian cancer cells, that C2 is also required for responsiveness to microtubule perturbing agents such as paclitaxel. Work from our laboratory has demonstrated that C2 is normally controlled by the metabolic status of the cell in that high levels of flux through the pentose phosphate pathway (PPP) prevents activation of C2 . This inhibition is exerted through phosphorylation of C2 at a specific residue that is catalyzed by calcium-calmodulin-dependent kinase II (CaMKII). CaMKII is activated by the product of the PPP, NADPH, through its ability to support fatty acid synthesis. The precise mechanism by which fatty acid synthesis activates CaMKII is not yet known. Because ovarian cancers exhibit increased glucose uptake and increased fatty acid synthesis, we hypothesized that susceptibility of ovarian cancers to front-line chemotherapeutic agents, reflect, at least in part, the metabolic status of the cells and, consequently, the phosphorylation state of caspase 2. We have found that inhibition of PPP operation and interference with fatty acid synthesis sensitizes ovarian cancer cells to a range of chemotherapeutic agents that depend upon C2 for cell death.