The activity and surface presence of organic cation/carnitine transporter OCTN2 (SLC22A5) in breast cancer cells depends on AKT kinase

L-carnitine is indispensable for transfer of fatty acids to mitochondria for the process of beta-oxidation, a process, whose significance in cancer has drawn attention in recent years. In humans majority of carnitine is delivered by diet and enters the cell due to activity of solute carriers (SLCs), mainly by ubiquitously expressed organic cation/ carnitine transporter (OCTN2/SLC22A5). In control and cancer human breast epithelial cell lines the major fraction of OCTN2 is present as a not matured non-glycosylated form. Studies on overexpressed OCTN2 demonstrated an exclusive interaction with SEC24C, as the cargo-recognizing subunit of coatomer II in trans- porter exit from endoplasmic reticulum. Co-transfection with SEC24C dominant negative mutant completely abolished presence of the mature form of OCTN2, pointing to a possibility of trafficking regulation. SEC24C was previously shown to be phosphorylated by serine/threonine kinase AKT, known to be activated in cancer. Further studies on breast cell lines showed that inhibition of AKT with MK-2206 in control and cancer lines decreased level of OCTN2 mature form. Proximity ligation assay showed that phosphorylation of OCTN2 on threonine was significantly abolished by AKT inhibition with MK-2206. Carnitine transport was positively correlated with the level of OCTN2 phosphorylated by AKT on threonine moiety. The observed regulation of OCTN2 by AKT places this kinase in the center of metabolic control. This points to both proteins, AKT and OCTN2, as druggable targets, in particular in a combination therapy of breast cancer.

Automated summary

L-carnitine plays a crucial role in the transfer of fatty acids to mitochondria for beta-oxidation, which has gained attention in cancer research. The majority of carnitine in humans comes from the diet and enters the cell through solute carriers, mainly the organic cation/carnitine transporter OCTN2/SLC22A5. Studies on breast epithelial cell lines showed that OCTN2 is present as a non-glycosylated form and is regulated by the protein SEC24C, which is phosphorylated by the kinase AKT. Inhibition of AKT decreased the level of mature OCTN2 and affected carnitine transport. This highlights the potential of AKT and OCTN2 as targets for combination therapy in breast cancer.