Nature Sub-Journal: New Target against Cancer - LUR1

TextsMansininhibits the synthesis of fatty acids in cancer cells as an anti-cancer therapy in the studyYet many clinical trials have failedA paper published June 1 in the journal Nature Metaboli reveals how cancer cells are constantly adjusting their metabolic mechanisms to combat resistance to fatty acid synthesis therapyThe study, led by Jason Moffat, a professor of molecular genetics at the University of Toronto in Canada, is the first to investigate overall genetic changes when cancer cells adapt to a shortage of key nutrients, such as fat or lipids that make up the outer membrane of the cell"If we can understand the adaptation mechanisms of cancer cells, we may be better able to target them and avoid the generation of drug resistance," said Michael Aregger, the first author of thepaper"
study found that when cancer cells are unable to produce their own lipids, they swallow lipids from the environment to ensure a stable supply of these essential building materials (in addition to building cell membranes, fat can also act as a chemical signal for fuel and cell-to-cell communication)This metabolic shift incancer cells is bad news for researchers trying to fight cancer by reducing fat reserves, especially for scientists who are developing FASN inhibitorsFASN is a fatty acid combination enzyme (fatty acid synthase) that is involved in the early steps of lipid synthesis and is being evaluated in patients with solid tumors such as breast cancer and colorectal cancer, targeting the protein, such as Sagimet/Glyse Pharmaceuticals TVB-2640fatty acids are precursors to larger lipid molecules, and the yield of fatty acids increases in many cancers due to higher FASN levelsIncreased FASN levels are also associated with poor prognosis in patientsTherefore, fatty acid synthesis is considered to be one of the most recommended metabolic pathwayshowever, the new study suggests that the effectiveness of FASN inhibitors may be short-lived because cancer can find another way to acquire lipids to block fatty acid synthesis, the researchers used a human cell line that removes FASN-coded genes Using the genome editing tool CRISPR, they removed all 18,000 human genes from the cell one by one to identify those that could compensate for the stagnant production of lipids analysis showed that hundreds of genes become critical when cells lack fat Their proteins are concentrated in known metabolic pathways through which cancer cells can absorb cholesterol and other lipids from their surroundings Since the process of cell intake of cholesterol was discovered half a century ago, it has become textbook knowledge, and the findings have not only won the Nobel Prize in Physiology or Medicine, but have also inspired the successful development of statins and many other drugs However, the new study reveals an unneglected part of the process: a gene previously named C12orf49 (also known as SPRING1) helps to activate a group of genes directly involved in lipid input In the study, the scientists renamed C12orf49 LUR1, the lipid intake regulator 1 (lipid uptake regulator 1) " We were pleasantly surprised to find that LUR1 was playing a role in regulating lipid intake, because we thought we were already at the helm of the process Aregger, the paper's first author, said The new findings by Aregger et al are validated by another paper published the same day in Nature Metabolism A new study from Rockefeller University in the United States also linked C12orf49 to lipid metabolism, further supporting the gene's role in this process In summary, these new studies reveal that LUR1 (C12orf49) is a new type of lipid metabolism steady state regulating factor Scientists believe that simultaneously inhibiting LUR1 (or other molecules involved in lipid input) and FASN, which targets both fat intake and fat synthesis, may lead to more effective cancer treatment This combination of treatments may not be easy to produce resistance because cells must overcome two obstacles at the same time: to overcome the blocking of fat "home-grown" and to overcome the blocking of fat "imports" Nature Metabolism's op-ed note sedatives point out that the discovery of the dependence of FASN defectcells on LUR1 (C12orf49) provides a very promising option for overcoming resistance to FASN inhibitors