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【medical-news】肺癌化疗抵抗的关键分子
Main Category: Lung Cancer News
Article Date: 15 Oct 2006 - 0:00am (PDT)
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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.
Co-authors include Anju Singh, Vikas Misra, Rajesh K Thimmulappa, Hannah Lee, Stephen Ames, Mohammad O. Hoque, James G. Herman, Stephen B. Baylin, David Sidransky, Edward Gabrielson and Malcolm Brock from Johns Hopkins.
1Nuclear factor erythroid-2 related factor 2 (NRF2)
2Kelch-like ECH-associated protein 1 (KEAP1) Scientists at Johns Hopkins have discovered how taking the brakes off a “detox” gene causes chemotherapy resistance in a common form of lung cancer.
Johns Hopkins科学家最近发现了一种普通肺癌中“解毒”基因怎样作用产生化疗抗性。
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.
NRF2基因产物能吸收香烟和柴油机废气等环境污染物并把它们排出细胞外，从而达到保护细胞目的。而另一个基因KEAR1编码的产物可阻止这个清洁过程。但是肺癌细胞却能破坏这类基因的表达从而阻止化疗药物的攻击。
“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.
我们发现肺癌细胞能够恢复和扭曲NRF2 and KEAP1基因表达从而帮助细胞免受化疗毒性作用。Johns Hopkins Bloomberg学校公共卫生和Kimmel癌症中心副教授，Shyam Biswal博士说。他的细胞培养研究结果发表在2006年10月3日的PLoS Medicine杂志上。
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作者:admin@医学,生命科学 2011-03-26 17:14
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