基于NF-kB和RSK-EphA2双重抑制作用的人参皂苷抗肿瘤转移的机理研究

Cancer is the major cause of death in China, and cancer metastasis is responsible for more than 90% of the deaths. There is, however, no anti-metastatic drug on the market. Therefore, elucidation of the whole molecular mechanisms regulating tumor metastasis is mandatory for the development of medicines. It has been shown chronic inflammation contributes to the onset of cancer. NF-kB activation is induced by inflammatory cytokines and promotes tumor malignant progression. On the other hand, receptor tyrosine kinases (RTKs) have been shown to have a critical role in the development and progression of many types of cancer. EphA2 belong to RTKs and overexpression of EphA2 is one of the prognostic factors in progressive tumors. We previous reported that TNF-a, which is an inflammatory cytokine, induces EphA2 phosphorylation on Ser-897 via ribosomal S6 kinase(RSK), and this novel pathway regulates migration and invasion of human cancer cells. Hence, inhibition of both the NF-kB and the RSK-EphA2 pathways should be a novel strategy for the inhibition of tumor metastasis, and a clinically applicable specific inhibitor to the both pathways must be an effective anti-metastasis agent. It has been reported that many kinds of ginsenosides have an anti-inflammatory effect via the inactivation of NF-kB signaling. Many studies have also shown ginsenosides relate to the inhibition of cancer metastasis by repression of NF-kB but the molecular mechanisms are still unclear. In this study, we aim to screen out the dual inhibitor of NF-kB and RSK-EphA2 from ginsenosides and elucidate its molecular mechanisms. The present study would be able to provide new information for pharmacological interventions.

目前癌症已居我国死因之首，90%以上的患者最终死于肿瘤转移。研究肿瘤转移的分子机制，对抗癌药物的研发至关重要。肿瘤转移的因素很多，慢性炎症是其中之一。它是通过激活NF-kB，使炎症病灶向肿瘤发展。此外，受体酪氨酸蛋白激酶EphA2可诱导肿瘤细胞增殖恶性转化。在我们前期研究中，炎症通路的激活可促进EphA2磷酸化，并首次发现TNF-a通过ERK-RSK通路诱导Ser-897磷酸化，同时Ser-897磷酸化信号可明显诱导肿瘤细胞转移。因此抑制EphA2中Ser-897磷酸化位点及NF-kB通路活性有望成为抑制肿瘤转移的新方法，寻找两者双重抑制剂对肿瘤转移的治疗尤为重要。研究表明，人参皂苷具有明显的抗炎、抗肿瘤作用。本项目拟从人参皂苷中筛选出既有抑制NF-kB活性，同时对RSK-EphA2磷酸化通路也有抑制作用的化合物，阐明其抗肿瘤转移机制，为临床抗肿瘤转移药物的开发提供科学依据。

目前癌症已居我国死因之首，90%以上的患者最终死于肿瘤转移。研究肿瘤转移的分子机制，对抗癌药物的研发至关重要。肿瘤转移的因素很多，慢性炎症是其中之一。它是通过激活NF-kB，使炎症病灶向肿瘤发展。此外，受体酪氨酸蛋白激酶EphA2可诱导肿瘤细胞增殖恶性转化。在我们前期研究中，炎症通路的激活可促进EphA2磷酸化，并首次发现TNF-a通过ERK-RSK通路诱导Ser-897磷酸化，同时Ser-897磷酸化信号可明显诱导肿瘤细胞转移。因此抑制EphA2中Ser-897磷酸化位点及NF-kB通路活性有望成为抑制肿瘤转移的新方法，寻找两者双重抑制剂对肿瘤转移的治疗尤为重要。研究表明，人参皂苷具有明显的抗炎、抗肿瘤作用。通过本项目的研究，从35个人参皂苷中筛选出既有抑制NF-kB活性同时对RSK-EphA2磷酸化通路也有抑制作用的化合物，重点研究了ginsenoside Rg5的作用机制，表明ginsenoside Rg5可同时与TAK1、TAB1及TAB2三种蛋白结合，降低total TAK1复合体的表达水平，一方面通过抑制TAK1及IKK磷酸化而抑制NF-kB (p65) Ser-536磷酸化；另一方面抑制ERK Thr-202/Tyr-204以及RSK Ser-380磷酸化来抑制TAK1活性以及抑制EphA2表达，发挥抑制EphA2磷酸化的作用。此外，ginsenoside Rg5降低EphA2蛋白的表达量并不是通过降低EphA2 mRNA的量和蛋白酶体介导的泛素化途径，而是通过溶酶体途径。本研究阐明的人参皂苷抗肿瘤转移机制，将为临床抗肿瘤转移药物的开发提供科学依据。