Nature Sub-Journal: New Target against Cancer - LUR1

Inhibiting fatty acid synthesis in cancer cells is an anti-cancer therapy in researchYet 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 therapySource: Nature Metabolism The 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 paper's first authorThe study found that when cancer cells are unable to produce their own lipids, they eat 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 in cancer 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 participates 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 (e.g., Sagimet/Coraypharmaceutical's TVB-2640)Fatty acids are precursors to larger lipid molecules, and the production 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 effectiveness of FASN inhibitors may be short-lived, however, because cancer can find another way to acquire lipidsTo block fatty acid synthesis, the researchers used a human cell line that removes FASN-coded genesUsing 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 lipidsAnalysis shows that hundreds of genes become critical when cells lack fatTheir proteins are concentrated in known metabolic pathways through which cancer cells can absorb cholesterol and other lipids from their surroundings The genetic interaction of C12orf49 indicates its role in lipid metabolism (Source: Nature Metabolism) 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 area that has been overlooked in this 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
LUR1 shuttles between the internal mesh and gorky body, regulating SREBF2 (the pathway regulates transcriptional reactions to lipid metabolism disorders) activation and lipid intake (Source: Natures Metabolim) "We were pleasantly surprised to find that LUR1 plays a role in regulating lipid intake, as we thought we were already at the helm Aregger, the paper's first author, said
Source: Nature Metabolism Aregger et al this new finding sedatiby in a separate 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 The gene interactions and co-needs networks of C12orf49 reflect their role in the SREBP pathway (Source: Natural Ebya, These new studies reveal that LUR1 (C12orf49) is a new type of lipid metabolism stabilization 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" The commentary issued by Nature Metabolism notes that the discovery of the dependence of FASN defectcells on LUR1 (C12orf49) provides a very promising option for overcoming resistance to FASN inhibitors Related paper: Michael Aregger et al Systematic mapping of the genetic interactions for de novo fatty acid synthesiss C12orf49 as a of regulator lipid simr Nature Metabolism (2020) Erol C Bayraktar et al Blycli co-co-sicards c12orf49 as a regulator of SREBP processing and simrai Nature Metabolism (2020)
Author: Man Source: PharmaKing Rubik's Cube Pro