异柠檬酸脱氢酶1（IDH1）在黑色素瘤适应内质网应激中的作用和分子机制

Melanoma, a malignant tumor, was largely resistant to most of therapeutic agents; one main reason is the adaption to ER Stress induced by the agents. So exploring the molecular mechanism of adaption is very important for the melanoma therapy. We analyzed the genes changed through microarray screen in melanoma cells under ER stress and found IDH1, one of isocitrate dehydrogenases, was remarkably up-regulated. IDH1 is a key enzyme in Krebs cycle and also critical for tumorgenesis. It is well-known that the change of its activity facilitates tumor growth; however its relationship with resistance to agents and its possible role in ER stress response are poorly understood. Therefore, in the program, we will focus on the role of IDH1 in adaption to ER stress and the mechanism for its upregulation; furthermore, we will uncover the potential pathway that IDH1 involved in and the relationship between its affected metabolic changes and ER stress. The study will provide novel knowledge for melanoma therapy and pharmaceutical innovation. ..

黑色素瘤作为一种高度恶性的肿瘤，对大部分肿瘤治疗药物具有明显的抵抗性；其中一个主要原因是黑色素瘤能够适应药物诱导的内质网应激，进而导致药物耐受；因此阐明其适应性的分子机制对于黑色素瘤的治疗具有重要意义。我们以黑色素瘤对内质网应激的适应性为切入点，通过mRNA 芯片分析，比较不同程度内质网应激引起的黑色素瘤细胞基因表达谱的变化，发现异柠檬酸脱氢酶IDH1的表达水平明显升高。IDH1在三羧酸循环中具有重要作用，与肿瘤发生关系密切，其酶活性改变可促进肿瘤的发生已被广泛研究，但是IDH1与黑色素瘤耐药性及适应内质网应激的关系还未见报道。本项目拟研究IDH1在黑色素瘤适应内质网应激中的作用；阐明内质网应激诱导IDH1上调的分子机制；揭示IDH1参与的信号通路及其诱发的代谢改变和内质网应激之间的关系。项目将为黑色素瘤的治疗和药物的研发提供一定的理论基础。

黑色素瘤作为一种高度恶性的肿瘤，对大部分肿瘤治疗药物具有明显的抵抗性；其中一个主要原因是黑色素瘤能够适应药物诱导的内质网应激，进而导致药物耐受；因此阐明其适应性的分子机制对于黑色素瘤的治疗具有重要意义。我们以黑色素瘤对内质网应激的适应性为切入点，通过mRNA 芯片分析，比较不同程度内质网应激引起的黑色素瘤细胞基因表达谱的变化，发现异柠檬酸脱氢酶IDH1的表达水平明显升高。增加的IDH1抑制黑色素瘤对低氧的适应能力，促进HIF1α的泛素化降解，导致HIF1α下游基因LDHA 和PDHK1的表达减少，促进细胞凋亡。进一步研究发现转录因子CHOP 和C/EBPβ可以直接结合在IDH1上游启动子上，促进IDH1的转录， 进而导致IDH1表达水平的增加。因此CHOP和C/EBPβ-IDH1-HIF1α信号通路在黑色素瘤发生发展过程中发挥重要的作用。通过我们研究揭示内质网应激诱导IDH1表达水平上升的分子机制，并且揭示增加的IDH1抑制黑色素瘤对低氧环境的适应能力，为黑色素瘤的临床治疗提供一定的理论基础。