PKM同工酶转变及PKM2小分子激动剂对肺癌糖代谢影响及其分子机制研究

Currently, lung cancer is the most common human malignant disease in the world. And it is the leading cause of cancer-related death. Cancer cells preferentially metabolize glucose by aerobic glycolysis, characterized by increased lactate production, which was called 'he Warburg effect'. There have been indications in the past that PKM2 might play a role in cellular growth stimulation and metabolic events. In addition, a large number of studies have found the closely relationship between lung cancer and hnRNP. However, few studies have concerned about the links of hnRNP and PKM among lung cancer. Our preliminary study found that the existence of consistency of hnRNP, PKM and the tumor proliferation. But it not enough to explain the phenomena completely, Therefore the role of PKM and its subtypes with hnRNP in the lung cancer proliferation and metastasis is worth studied. Recent studies demonstrate that PKM2 responds to oxidative stress. The diminishes PKM2 activity, decreasing pyruvate formation and increasing flux of glycolytic metabolites into the pentose phosphate pathway. This pathway produces reduced nicotinamide adenine dinucleotide phosphate (NADPH), This was especially important under hypoxia, a characteristic of most solid tumor microenvironments. It suggested that small-molecule activators of PKM2 would be a new way of lung cancer therapy by limiting the ability of glycolytic intermediates to fuel the pentose phosphate pathway. Therefore, further explore the role of the PKM2 the small molecule agonists of the tumor oxidative stress will find new ways of prevention and treatment of lung cancer.

肺癌是当前世界上最常见的人类恶性肿瘤，其死亡率居癌症相关死因的首位。肿瘤细胞的特殊性在于它们存在Warburg 效应。丙酮酸（PKM）为糖酵解的主要产物，它与癌基因、细胞代谢、肿瘤过度增殖密切相关；既往有研究发现肺癌细胞和hnRNP密切相关，但是关于hnRNP、PKM与肺癌三者联系研究甚少。我们前期的研究发现hnRNP-PKM-肺癌细胞增殖变化存在一致性。由于hnRNP参与mRNA的剪接，它与PKM同工酶的转变可能存在内在联系,但机制不明，推测hnRNP导致PKM1转化为PKM2从而影响肺癌增殖与转移，值得进一步探讨。同时肿瘤细胞受到肿瘤微环境作用，有研究表明缺氧可以加剧细胞中PKM2对抗ROS的过程中发挥的支持作用，通过戊糖途径介导产生NADPH，增加细胞氧化还原缓冲能力，从而增强细胞生存能力，于是进一步探究PKM2小分子激动剂在肿瘤氧化应激中的作用将为寻找肺癌防治的新途径提供更多的思路

肺癌是当前世界上最常见的人类恶性肿瘤，其死亡率居癌症相关死因的首位。肿瘤细胞的特殊性在于它们存在Warburg 效应。丙酮酸（PKM）为糖酵解的主要产物，它与癌基因、细胞代谢、肿瘤过度增殖密切相关；既往有研究发现肺癌细胞和hnRNP 密切相关，我们成功构建了hnRNP抑制的质粒，并将其导入肺癌A549细胞，SK-MES-1细胞与NCI-H460细胞干扰重组质粒可以稳定抑制hnRNP B1基因表达，除A549细胞，其它几个细胞系hnRNPB1干扰没有对PKM1/PKM2影响；检测中还发现A549细胞、SK-MES细胞、NCI-H460、NCI-H1395细胞PKM1表达量很低推测hnRNPB1对细胞增殖的影响可能不是由PKM1/PKM2转变而来。另外我们研究发现在鳞癌中ｈｎＲＮＰＢ１较为丰富，而在腺癌中PKM１／PKM２比值最低。也许可以进一步以此为切入点进一步分析，以观察其分布及与疾病预后转归的关系。