Nencki Institute of Experimental Biology of Polish Academy of Sciences, 3 Pasteur Street, 02-093, Warsaw, Poland.
Arch Biochem Biophys. 2023 Jul 1;742:109616. doi: 10.1016/j.abb.2023.109616. Epub 2023 May 13.
l-carnitine is indispensable for transfer of fatty acids to mitochondria for the process of β-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 transporter 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.
左旋肉碱对于脂肪酸向线粒体的转运是必不可少的，这一过程在近年来因其在癌症中的重要性而引起了关注。在人类中，大部分肉碱是通过饮食提供的，并且由于溶质载体（SLCs）的活性进入细胞，主要是通过广泛表达的有机阳离子/肉碱转运体（OCTN2/SLC22A5）。在对照和癌症人乳腺上皮细胞系中，OCTN2 的主要部分以不成熟的非糖基化形式存在。对过表达的 OCTN2 的研究表明，它与 SEC24C 具有独特的相互作用，SEC24C 是衣被小泡 II 的货物识别亚基，在转运体从内质网中输出。与 SEC24C 显性负突变体的共转染完全消除了 OCTN2 的成熟形式的存在，这表明存在运输调节的可能性。SEC24C 以前被证明可以被丝氨酸/苏氨酸激酶 AKT 磷酸化，AKT 在癌症中被激活。对乳腺细胞系的进一步研究表明，在对照和癌症系中用 MK-2206 抑制 AKT 会降低 OCTN2 成熟形式的水平。邻近连接分析表明，用 MK-2206 抑制 AKT 显著消除了 OCTN2 上苏氨酸的磷酸化。肉碱转运与 AKT 磷酸化的 OCTN2 水平呈正相关。AKT 对 OCTN2 的调节将这种激酶置于代谢控制的中心。这表明 AKT 和 OCTN2 这两种蛋白质都是可药物靶向的，特别是在乳腺癌的联合治疗中。
