美国约翰·霍普金斯大学的研究人员日前发现了抑制人体NRF2基因等“脱毒”基因、进而导致肺癌化疗抗性的机制。这项研究的结果刊登在10月3日出版的《公共科学图书馆·医学》（PLoSMedicine）杂志上。
约翰·霍普金斯Bloomberg公共卫生学院和Kimmel癌症中心的助理教授Shyam Biswal博士等人发现，由NRF2基因编码的产物通常能够保护细胞不受环境污染物如香烟烟雾和油烟侵害，它能吸收并将这些物质“泵”出细胞。它还能促使细胞排出有害化合物。另外一个被称为KEAP1的基因编码的产物能够中止这种清理过程。但是肺癌细胞能破坏后者的表达，从而产生抵抗化疗药物攻击肿瘤细胞的作用。
这项研究探索了肺癌细胞如何破坏KEAP1的表达来帮助肿瘤细胞逃避化疗药物对其攻击的过程。他们发现，NRF2基因能够编码一种启动蛋白质——它能启动另外一些能清除毒素的蛋白质和酶的制造。为了中止脱毒过程，由KEAP1基因编码的蛋白质能够与NRF2基因制造的这种启动蛋白质结合，并将它们标记成需要摧毁的蛋白质。在肺癌细胞中，NRF2基因的活性异常活跃，它能将所有细胞毒素清除掉，包括化疗药物。Biswal表示，抑制NRF2基因的活性可能改善现有化疗药物的疗效，尤其是广泛用于治疗肺癌的含铂化合物。
在Biswal的研究中，6个肺癌细胞系和54个非小细胞肺癌患者组织样本中的10个样本都携带突变的KEAP1基因。这种突变使该基因失活，使其无法控制NRF2基因产生的脱毒过程。另外，其中一半的组织样本中丢失了KEAP1基因的一个拷贝，而这些患者的正常肺脏组织中没有出现基因拷贝的丢失或突变。NRF2的活性和它编码的“清毒”蛋白和酶的活性在肿瘤样本中要比正常的细胞中高。细胞培养检测也显示，携带突变的KEAP1基因的癌细胞对化疗药物的抵抗性比正常肺细胞的要强。而携带正常KEAP1基因的肿瘤样本也表现出NRF2基因表达增强了，这表明了存在分解KEAP1基因的其他途径，如对该基因进行拼接来产生较短的、无活性的蛋白质。
接下来，研究人员打算在更大的样本分析试验中验证这些发现，然后筛选合适的抗癌新药物。
英文原文：
KEY TO LUNG CANCER CHEMO RESISTANCE REVEALED
Scientists at Johns Hopkins have discovered how taking the brakes off a “detox” gene causes chemotherapy resistance in a common form of lung cancer.
Products made by a gene called NRF2 normally protect cells from environmental pollutants like cigarette smoke and diesel exhaust by absorbing the materials and pumping them out of the cell. Another gene called KEAP1 encodes products that stop this cleansing process. But lung cancer cells sabotage the expression of these same genes to block assault from chemotherapy drugs.
“What we’re seeing is that lung cancer cells recruit and distort NRF2 and KEAP1 expression to help tumor cells evade the toxic effects of chemotherapy,” says Shyam Biswal, Ph.D., associate professor at the Johns Hopkins Bloomberg School of Public Health and Kimmel Cancer Center, who published results of cell culture studies in the October 3, 2006 issue of PLoS Medicine.
Past studies have shown that NRF2 detoxifies cells by directing proteins to absorb and pump out pollutants and chemicals. The NRF2 gene makes a “trigger” protein which starts the production of other proteins and enzymes that sweep the cell clear of toxins. To halt the detox process, proteins manufactured by KEAP1 bind to the NRF2 triggers tagging them for destruction. In cancer cells, NRF2 activity runs amok, sweeping away all cellular toxins, including chemotherapy agents.
Biswal says that blocking NRF2 activity could improve the effectiveness of standard chemotherapy drugs, particularly platinum-based compounds widely used for lung cancer.
In Biswal’s study, half of 12 lung cancer cell lines and 10 of 54 tissue samples from non-small cell lung cancer patients had mutations in the KEAP1 gene rendering it inactive and unable to keep NRF2 activity in check. In addition, half of the tissue samples were missing one copy of the KEAP1 gene – cells usually have two copies of each gene. No missing genes or mutations were observed in normal lung tissues from the same patients.
NRF2 activity along with its cleansing proteins and enzymes were higher in tumor samples than normal cells, according to the researchers. Their cell culture tests also show that cancer cells with KEAP1 mutations are more resistant to chemotherapy drugs than normal lung cells.
Tumor samples with normal KEAP1 genes also show increased levels of NRF2 and its enzymes, suggesting other ways of dismantling KEAP1, such as splicing the gene to make a shortened, ineffective protein, he said.
The researchers plan to confirm their findings with a larger set of samples and then to screen for appropriate drugs. Funding for the study was provided by the National Cancer Institute Lung SPORE (Specialized Program of Research Excellence), National Heart Lung and Blood Institute, National Institute of Environmental Health Sciences Center, National Institute of Health, and the Flight Attendant Medical Research Institution.
