Zhou Weibo, Han Wan Fang, Landree Leslie E, Thupari Jagan N, Pinn Michael L, Bililign Tsion, Kim Eun Kyoung, Vadlamudi Aravinda, Medghalchi Susan M, El Meskini Rajaa, Ronnett Gabriele V, Townsend Craig A, Kuhajda Francis P
Departments of Pathology, Neuroscience, Neurology, Oncology, and Biological Chemistry, The Johns Hopkins University School of Medicine, USA.
Cancer Res. 2007 Apr 1;67(7):2964-71. doi: 10.1158/0008-5472.CAN-06-3439.
Fatty acid synthase (FAS), the enzyme responsible for the de novo synthesis of fatty acids, is highly expressed in ovarian cancers and most common human carcinomas. Inhibition of FAS and activation of AMP-activated protein kinase (AMPK) have been shown to be cytotoxic to human cancer cells in vitro and in vivo. In this report, we explore the cytotoxic mechanism of action of FAS inhibition and show that C93, a synthetic FAS inhibitor, increases the AMP/ATP ratio, activating AMPK in SKOV3 human ovarian cancer cells, which leads to cytotoxicity. As a physiologic consequence of AMPK activation, acetyl-CoA carboxylase (ACC), the rate-limiting enzyme of fatty acid synthesis, was phosphorylated and inhibited whereas glucose oxidation was increased. Despite these attempts to conserve energy, the AMP/ATP ratio increased with worsening cellular redox status. Pretreatment of SKOV3 cells with compound C, an AMPK inhibitor, substantially rescued the cells from C93 cytotoxicity, indicating its dependence on AMPK activation. 5-(Tetradecyloxy)-2-furoic acid, an ACC inhibitor, did not activate AMPK despite inhibiting fatty acid synthesis pathway activity and was not significantly cytotoxic to SKOV3 cells. This indicates that substrate accumulation from FAS inhibition triggering AMPK activation, not end-product depletion of fatty acids, is likely responsible for AMPK activation. C93 also exhibited significant antitumor activity and apoptosis against SKOV3 xenografts in athymic mice without significant weight loss or cytotoxicity to proliferating cellular compartments such as bone marrow, gastrointestinal tract, or skin. Thus, pharmacologic FAS inhibition selectively activates AMPK in ovarian cancer cells, inducing cytotoxicity while sparing most normal human tissues from the pleiotropic effects of AMPK activation.
脂肪酸合酶（FAS）是负责从头合成脂肪酸的酶，在卵巢癌和大多数常见人类癌症中高度表达。已证明抑制FAS和激活AMP活化蛋白激酶（AMPK）在体外和体内对人类癌细胞具有细胞毒性。在本报告中，我们探讨了FAS抑制的细胞毒性作用机制，并表明合成的FAS抑制剂C93可增加AMP/ATP比值，激活SKOV3人卵巢癌细胞中的AMPK，从而导致细胞毒性。作为AMPK激活的生理结果，脂肪酸合成的限速酶乙酰辅酶A羧化酶（ACC）被磷酸化并受到抑制，而葡萄糖氧化增加。尽管有这些节约能量的尝试，但随着细胞氧化还原状态的恶化，AMP/ATP比值仍会增加。用AMPK抑制剂化合物C预处理SKOV3细胞可使细胞从C93细胞毒性中得到显著挽救，表明其对AMPK激活的依赖性。5-（十四烷氧基）-2-呋喃甲酸是一种ACC抑制剂，尽管抑制了脂肪酸合成途径活性，但并未激活AMPK，对SKOV3细胞也无明显细胞毒性。这表明FAS抑制引发AMPK激活导致的底物积累而非脂肪酸终产物的耗竭可能是AMPK激活的原因。C93对无胸腺小鼠体内的SKOV3异种移植瘤也表现出显著的抗肿瘤活性和诱导凋亡作用，且对骨髓、胃肠道或皮肤等增殖细胞区室无明显体重减轻或细胞毒性。因此，药物性FAS抑制在卵巢癌细胞中选择性激活AMPK，诱导细胞毒性，同时使大多数正常人体组织免受AMPK激活的多效性影响。
