SLC22A5 (OCTN2) Carnitine Transporter-Indispensable for Cell Metabolism, a Jekyll and Hyde of Human Cancer

Abstract

Oxidation of fatty acids uses l-carnitine to transport acyl moieties to mitochondria in a so-called carnitine shuttle. The process of β-oxidation also takes place in cancer cells. The majority of carnitine comes from the diet and is transported to the cell by ubiquitously expressed organic cation transporter novel family member 2 (OCTN2)/solute carrier family 22 member 5 (SLC22A5). The expression of SLC22A5 is regulated by transcription factors peroxisome proliferator-activated receptors (PPARs) and estrogen receptor. Transporter delivery to the cell surface, as well as transport activity are controlled by OCTN2 interaction with other proteins, such as PDZ-domain containing proteins, protein phosphatase PP2A, caveolin-1, protein kinase C. SLC22A5 expression is altered in many types of cancer, giving an advantage to some of them by supplying carnitine for β-oxidation, thus providing an alternative to glucose source of energy for growth and proliferation. On the other hand, SLC22A5 can also transport several chemotherapeutics used in clinics, leading to cancer cell death.

Keywords: Carnitine; SLC22A5/OCTN2; cancer.

Figure 1

Fatty acid oxidation processes involving carnitine in mammalian cell. For a detailed description and abbreviations see the text. FAO, fatty acid oxidation.

Figure 2

Presence of Octn2 in the blood-brain barrier. Rat brain slices were obtained, fixed and embedded in Epon after dehydration, as presented in [30]. They were subsequently treated with anti-OCTN2 antibody and the secondary antibody coupled to 10 nm gold particles, as presented in [12]. The areas with selected capillaries are shown. The TJ, tight junction; single arrow, Octn2 in the apical membrane. Octn2 is also detected in astrocytic endfeet (right panel). The bar size: 200 nm.

Figure 3

Regulation of SLC22A5/OCTN2 in the mammalian cell. A. Transcription of SLC22A5; B. Interaction of SLC22A5/OCTN2 with PDZ proteins; C. Trafficking to the plasma membrane-interaction with phosphatase PP2A; D. Lateral movement in the plasma membrane to rafts. For a detailed description and abbreviations see the text.

Figure 4

Probabulity of overall survival (OS) in breast cancer patients expressing high or low SLC22A5 levels. A. OS from Human protein Atlas with auto-selected best cutoff; mRNA data collected with RNA seq; B. OS assessed with the use of KMplotter and its PAN Cancer RNA seq dataset, with auto-selected best cutoff; C. OS assessed with the use of KMplotter and its Breast Cancer Affymetrix gene chip dataset, with auto-selected best cutoff; D. SLC22A5 expression in breast cancer ER− and ER+ samples from CANCERTOOL and dataset from [105]; E. OS assessed with the use of KMplotter and its Breast Cancer Affymetrix gene chip dataset restricted only to ER− patients, with auto-selected best cutoff; F. OS assessed with the use of KMplotter and its Breast Cancer Affymetrix gene chip dataset restricted only to ER+ patients, with auto-selected best cutoff. Graphic illustrations taken from proteinatlas.org, web.bioinformatics.cicbiogune.es/CANCERTOOL/and Kmplot.com.