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.

Carnitine Traffic in Cells. Link With Cancer

“…In particular, exosomes derived from HEK293 cells treated with interferon-γ (INF-γ) carry a higher amount of OCTN2 with respect to exosomes derived from untreated cells. This correlates well with the suggestion that carnitine is involved in the inflammatory response and that the expression of OCTN2 in epithelia can be modulated by inflammatory cytokines such as INF-γ and TNF-α (Console et al, 2018;Juraszek and Nalecz, 2019;Pochini et al, 2019).…”

“…For instance, the mitochondrial "shuttle-system" allows the transport of fatty acids, as acylcarnitines, from the cytosol into the mitochondrial matrix where these nutrients are oxidized for ATP production. Similar shuttles have been proposed in peroxisomes or the endoplasmic reticulum (ER), but definitive demonstrations of their existence are still lacking (Tonazzi et al, 2006;Pochini et al, 2013;Demarquoy and Le Borgne, 2015;Juraszek and Nalecz, 2019).…”

“…Besides intestine and kidney, OCTN2 is expressed in several tissues such as placenta, mammary gland, liver, heart, testis, skeletal muscle, and brain, where it is also expressed at the level of the bloodbrain barrier (BBB; Koepsell, 2013;Pochini et al, 2019;Koepsell, 2020). In good agreement with the localization of OCTN2 in the brain, the administration of carnitine-derivatives may sustain neuroprotection (Juraszek and Nalecz, 2019;Pochini et al, 2019). The carnitine transport mediated by OCTN2 is Na +dependent.…”

“…In this respect, the N-glycosylation pathway (Filippo et al, 2011), as well as a more complicated process involving a multiprotein complex that traffics OCTN2 to the definitive location, have been described (Jurkiewicz et al, 2017). Interestingly, the interactions with the scaffold proteins PDZK1 and PDZK2 have been described as begin responsible for the regulation of both rat and human OCTN2 transport function (Kato et al, 2005;Juraszek and Nalecz, 2019). The possible transport mechanisms together with the wide tissue distribution underlie the role of OCTN2 as the major transporter responsible for the traffic of carnitine and carnitine derivatives in the intestine, distribution to several body districts and reabsorption/excretion in the kidney (Figure 2).…”

“…To date, several studies reported a link between the altered expression of OCTN2 and cancer development and progression (Lu et al, 2008;Scalise et al, 2012;Wang et al, 2012;Elsnerova et al, 2016;Lee et al, 2016;Fink et al, 2019;Juraszek and Nalecz, 2019; Table 1). Interestingly, its expression is found up or down-regulated depending on the carbon source that the tumors use to produce energy.…”