Glycerol-3P-acyltransferase 2 counteracts the apoptotic effect of arachidonic acid and modulates the expression of genes that influence cell migration and invasion

MOSCOSO, VERONICA; FIORELLA FERREMI; MAURO MONTANARO

Mendoza

Congreso; Congreso SAIB 2022; 2022

Sociedad Argentina de Investigaciones en Bioquímica y Biología Molecular

Glycerol-3P-acyltransferase 2 (GPAT2) features the most dissimilar expression profile among all other GPAT enzymes found in mammals, restricting its normal function mainly to sperm cells and away from classic lipogenic tissues, in contrast to GPAT1, 3, and 4. Surprisingly, we also found a role for our gene of interest in cellular models of breast and colon cancer, where it contributes to the establishment of a more tumorigenic scenario through the stimulation of cell proliferation, anchorage-independent growth, and tumorigenic features both in-vitro and in mouse experiments. We have also shown that GPAT2 gene is able to act via the modulation of several cancer-related metabolic pathways and both short and long non-coding RNAs.With the aim of getting new insights into the cellular mechanisms linking high GPAT2 expression to increased tumor-related phenotype on MDA-MB-231 human triple-negative breast cancer cells, we studied the changes in invasion and migration behaviors induced by this gene at the cellular and genetic levels. Because the increase in the apoptotic index in response to arachidonic acid (AA) is one of the most relevant modifications after GPAT2 silencing, we analyzed those pathways implicated in AA usage and investigated the modulation of the activity of caspases belonging to extrinsic and intrinsic apoptotic pathways.We found an alteration in the expression of genes involved in extracellular matrix degradation and cytoskeleton organization which can explain, at least partially, the increase in invasion and migration properties for cells expressing GPAT2 at a higher level. Our results also show a modulation on the expression levels of genes coding for AA metabolism and apoptosis-related enzymes that correlate to a diminished apoptotic effect of AA supplementation for those cells expressing higher GPAT2 amount.Altogether, these results provide new data supporting the consideration of GPAT2 expression as a poor prognostic factor for breast cancer patients.