网膜转移过程中卵巢癌细胞调节AMPK及TAK1/NF-κB 信号通路的机制和意义研究

Ovarian cancer is a common and the most lethal gynecological malignancy among women. The high mortality rate of this disease is due to poor prognosis and most patients present at an advanced stage. Metastatic dissemination is a common occurrence of advanced-stage ovarian cancer and usually causes critical problem in clinical management. The omentum is an adipose tissue and ovarian cancer cells preferentially metastasize to this organ. However, the underlying molecular mechanisms for the dynamic interplay of omentum and ovarian cancer cells remain unknown. Our preliminary study using an omental explant culture system (OCM) demonstrated that ovarian cancer cells co-cultured with OCM exhibited an increase in in vitro cell growth, cell migration and invasion through activation of TAK1 and NFkB signaling activity. Intriguingly, an increase of Acetyl-CoA Carboxylase activity (phospho-ACC) was also observed, indicating the tumor cells synthesized ATP cellular energy by fatty acid oxidation for the rapid cell growth. However, AMPK acts as an upstream of ACC, only slight elevated initially and progressively reduced. The reduced AMPK activity led to an increase of TAK1 and NFkB signaling activities in a time dependent manner upon treatment of OCM. In contrast, co-treatment of metformin, a known AMPK activator, or blocking TAK1/NFkB signaling cascade using TAK1 specific inhibitor, (5Z) -7-Oxozeaenol, could remarkably inhibit OCM-mediated cell growth, cell migration and invasion of ovarian cancer cells. Based on these preliminary findings, we hypothesize that the omentum provides fatty acid as energy fuel for fast-growing ovarian cancer cells, while the metabolic reprogramming of ovarian cancer cells by inhibition of AMPK activity activates TAK1/NFkB signaling axis which crucially promotes the tumor growth and omental metastasis of ovarian cancer. To prove our hypothesis, this proposed study aims 1) to investigate the effects of the omental microenvironment on ovarian cancer cell metabolism and how of the ovarian cancer cell responses in maintaining their cell growth rate; 2) to characterize the molecular mechanisms of AMPK in governing TAK1/NFkB signaling cascade; and 3) to examine the functional roles of AMPK and TAK1/NFkB signaling in metastatic colonization in vitro and in vivo. We strongly believe that our proposed works may unveil the mechanisms explaining the dynamic interaction of the omental microenvironment and ovarian cancer cell metabolism and oncogenic capacities. These data may provide a scientific basis for developing therapeutic interventions to impede ovarian cancer metastasis.

卵巢癌是常见且死亡率高的妇科恶性肿瘤，难以早期诊断导致其在发现时多己发展至晚期。晚期卵巢癌多发生网膜转移，然而原因尚不明确。初步研究显示网膜条件培养基(OCM)培养的卵巢癌细胞能有效提高代谢重编程激活脂肪酸氧化合成ATP，同时抑制AMPK活性以激活TAK1/NF-κB信号途径来促进卵巢癌细胞生长，迁移和侵袭。进一步研究发现AMPK激活剂或TAK1抑制剂均能显著抑制OCM介导的卵巢癌细胞生长，迁移和侵袭。因此我们推测网膜为卵巢癌细胞提供脂肪酸作为能量来源，同时抑制AMPK活性以激活TAK1/NF-κB信号途径来促进在网膜上的生长。本课题拟进一步研究卵巢癌细胞如何代谢重编程以适应网膜微环境并维持生长速率，AMPK调控TAK1/NFκB信号通路的分子机制， 和AMPK/TAK1/NFκB信号通路在肿瘤种植转移中的功能。本研究将揭示网膜微环境与癌细胞代谢再编程及其致瘤特性之间相互作用的动态机制。

卵巢癌是一种腹腔内肿瘤，腹水微环境可以增强卵巢癌细胞的侵袭性和传播，并与预后不良有关。然而，卵巢癌细胞在腹水微环境中代谢改变的重要性仍不清楚。本题研究结果显示卵巢癌细胞通过脂质代谢的重编程，在腹水微环境中表现出增强的侵袭性。比较蛋白质组学分析显示，当在腹水微环境中培养时，脂质代谢在卵巢癌细胞中具有高活性，表明从有氧糖酵解到β-氧化和脂肪生成的代谢转变。由于高ATP产生的反馈效应导致的AMPK活性降低导致mTOR和TAK1 / NF-κB信号传导的显着活化，这反过来增强了癌症生长。值得注意的是，低毒性AMPK激活剂，TAK1抑制剂和FASN抑制剂的鸡尾酒治疗法可显著降低卵巢癌的致癌特性，甚至杀死卵巢癌细胞，而不影响器官的健康。因此，靶向脂质代谢信号轴可以阻止卵巢癌腹膜转移。