EFFECT OF 9-HYDROXY-STEARIC ACID ON GLUCOSE METABOLISM IN A HUMAN COLON CANCER CELL LINE

Recent findings identified a new class of endogenous lipids, branched Fatty Acid esters of Hydroxy Fatty Acids (FAHFAs), able to behave as specific signaling molecules that can regulate the cellular metabolism [1]. Among FAHFAs, the Palmitic-Acid-9-Hydroxy-Stearic Acid (9-PAHSA) seems to exert favorable metabolic effects in obesity-related diseases and type 2 diabetes, causing an increase in insulin sensitivity and glucose uptake. It has been recently reported that the FAHFAs content in human serum of breast cancer patients was significantly decreased compared to healthy controls [2], thus it is very interesting to investigate the possible involvement of these lipid molecules also in cancer transformation and progression. Previous studies of our research group have shown that the administration of 9-hydroxy-stearic acid (9-HSA) to colon carcinoma cells (HT29) induces strong antiproliferative and differentiating effects, with a cell cycle arrest in G0/G1 phase [3]. Since 9-HSA can be produced by the hydrolysis of 9-PAHSA, it is conceivable that also this lipid could act as signaling molecule. Consequently, the aim of this research was the characterization of the glucose metabolism of HT29 cells treated with 9-HSA. As a first step, the effect of 9-HSA on the lipid organization of HT29 cells was studied, showing an increase of the fluidity of plasma membrane. The treatment of HT29 with 9-HSA for 1 h provokes a significant increase of the glucose transporter Glut1 (and in a lesser extent of Glut3) on the plasma membrane, as a result of a translocation from intracellular stores, since the level of expression of the two transporters were unchanged, as determined by RT-PCR. Accordingly, the higher amount of Glut1 on the cell surface caused also an increase in glucose uptake into the cells. RT-PCR analysis showed also a significant increase of MCT1, the monocarboxylate transporter, in HT29 cells treated with 9-HSA. MCT1 is commonly overexpressed by cancer cells to maintain lactate and pH homeostasis [4]. Therefore, lactate production was measured in HT29 cells upon 9-HSA treatment for 1 h. Results show that lactate production was significantly increased, indicating a cellular metabolic shift toward glycolysis. The acute metabolic changes observed in HT29 cells are typical cellular responses to a signal molecule, supporting the hypothesis of a signaling role for 9-HSA in cancer cells. 1. M.M. Yore et al. Cell, 159:318-332, 2014. 2. Q.F. Zhu et al., J. Chromatogr. B, 1061-1062:34-40, 2017. 3. N. Calonghi et al., Biochem. Biophys. Res. Commun., 314:138-142, 2004 4. J. Adijanto and N.J. Philp, Curr. Top. Membr., 70:275-311, 2012.