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 tumour 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.
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.
In Biswal's study, half of twelve lung cancer cell lines and ten 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 tumour 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, Biswal concluded.
MEDICA.de; Source: Johns Hopkins University