美國約翰·霍普金斯大學(xué)的研究人員日前發(fā)現(xiàn)了抑制人體NRF2基因等“脫毒”基因、進(jìn)而導(dǎo)致肺癌化療抗性的機(jī)制,。這項(xiàng)研究的結(jié)果刊登在10月3日出版的《公共科學(xué)圖書館·醫(yī)學(xué)》（PLoSMedicine）雜志上,。
約翰·霍普金斯Bloomberg公共衛(wèi)生學(xué)院和Kimmel癌癥中心的助理教授Shyam Biswal博士等人發(fā)現(xiàn),，由NRF2基因編碼的產(chǎn)物通常能夠保護(hù)細(xì)胞不受環(huán)境污染物如香煙煙霧和油煙侵害，它能吸收并將這些物質(zhì)“泵”出細(xì)胞,。它還能促使細(xì)胞排出有害化合物,。另外一個被稱為KEAP1的基因編碼的產(chǎn)物能夠中止這種清理過程。但是肺癌細(xì)胞能破壞后者的表達(dá),，從而產(chǎn)生抵抗化療藥物攻擊腫瘤細(xì)胞的作用,。
這項(xiàng)研究探索了肺癌細(xì)胞如何破壞KEAP1的表達(dá)來幫助腫瘤細(xì)胞逃避化療藥物對其攻擊的過程。他們發(fā)現(xiàn),，NRF2基因能夠編碼一種啟動蛋白質(zhì)——它能啟動另外一些能清除毒素的蛋白質(zhì)和酶的制造,。為了中止脫毒過程，由KEAP1基因編碼的蛋白質(zhì)能夠與NRF2基因制造的這種啟動蛋白質(zhì)結(jié)合,，并將它們標(biāo)記成需要摧毀的蛋白質(zhì),。在肺癌細(xì)胞中，NRF2基因的活性異?；钴S,，它能將所有細(xì)胞毒素清除掉，包括化療藥物,。Biswal表示,，抑制NRF2基因的活性可能改善現(xiàn)有化療藥物的療效，尤其是廣泛用于治療肺癌的含鉑化合物,。
在Biswal的研究中,，6個肺癌細(xì)胞系和54個非小細(xì)胞肺癌患者組織樣本中的10個樣本都攜帶突變的KEAP1基因。這種突變使該基因失活,，使其無法控制NRF2基因產(chǎn)生的脫毒過程,。另外，其中一半的組織樣本中丟失了KEAP1基因的一個拷貝,，而這些患者的正常肺臟組織中沒有出現(xiàn)基因拷貝的丟失或突變,。NRF2的活性和它編碼的“清毒”蛋白和酶的活性在腫瘤樣本中要比正常的細(xì)胞中高。細(xì)胞培養(yǎng)檢測也顯示,，攜帶突變的KEAP1基因的癌細(xì)胞對化療藥物的抵抗性比正常肺細(xì)胞的要強(qiáng),。而攜帶正常KEAP1基因的腫瘤樣本也表現(xiàn)出NRF2基因表達(dá)增強(qiáng)了,，這表明了存在分解KEAP1基因的其他途徑，如對該基因進(jìn)行拼接來產(chǎn)生較短的,、無活性的蛋白質(zhì),。
接下來，研究人員打算在更大的樣本分析試驗(yàn)中驗(yàn)證這些發(fā)現(xiàn),，然后篩選合適的抗癌新藥物,。
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.
