Scientists have engineered cells with a 'built-in genetic circuit' which produces a molecule that inhibits the ability of tumours to survive and grow in their low oxygen environment. The genetic circuit produces the machinery necessary for the production of a compound that inhibits a protein which has a significant and critical role in the growth and survival of cancer cells. This results in the cancer cells being unable to survive in the low oxygen, low nutrient tumour micro-environment. As tumours develop and grow, they rapidly outstrip the supply of oxygen delivered by existing blood vessels.
This results in cancer cells needing to adapt to low oxygen environment. To enable them to survive and grow in the low-oxygen or 'hypoxic' environments, tumours contain increased levels of a protein called Hypoxia-inducible factor 1 (HIF-1). HIF-1 senses reduced oxygen levels and triggers many changes in cellular function, including a changed metabolism and sending signals for the formation of new blood vessels. It is thought that tumours primarily hijack the function of this protein (HIF-1) to survival and grow. "In an effort to better understand the role of HIF-1 in cancer, and to demonstrate the potential for inhibiting this protein in cancer therapy, we engineered a human cell line with an additional genetic circuit that produces the HIF-1 inhibiting molecule when placed in a hypoxic environment," said Ali Tavassoli, professor at the University of Southampton in the UK. "We've been able to show that the engineered cells produce the HIF-1 inhibitor, and this molecule goes on to inhibit HIF-1 function in cells, limiting the ability of these cells to survive and grow in a nutrient-limited environment as expected," said Tavassoli. "In a wider sense, we have given these engineered cells the ability to fight back - to stop a key protein from functioning in cancer cells," he said. "This opens up the possibility for the production and use of sentinel circuits, which produce other bioactive compounds in response to environmental or cellular changes, to target a range of diseases including cancer," said Tavassoli. The genetic circuit is incorporated onto the chromosome of a human cell line, which encodes the protein machinery needed for the production of their cyclic peptide HIF-1 inhibitor. The production of the HIF-1 inhibitor occurs in response to hypoxia in these cells. The research team demonstrated that even when produced directly in cells, this molecule still prevents the HIF-1 signalling and the associated adaptation to hypoxia in these cells. "The main application for this work is that it eliminates the need for the synthesis of our inhibitor, so that biologists conducting research into HIF function can easily access our molecule and hopefully discover more about the role of HIF-1 in cancer," said Tavassoli. The study was published in the journal ACS Synthetic Biology.
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