Membrane transporters in cell physiology, cancer metabolism and drug response

Abstract

By controlling the passage of small molecules across lipid bilayers, membrane transporters influence not only the uptake and efflux of nutrients, but also the metabolic state of the cell. With more than 450 members, the Solute Carriers (SLCs) are the largest transporter super-family, clustering into families with different substrate specificities and regulatory properties. Cells of different types are, therefore, able to tailor their transporter expression signatures depending on their metabolic requirements, and the physiological importance of these proteins is illustrated by their mis-regulation in a number of disease states. In cancer, transporter expression is heterogeneous, and the SLC family has been shown to facilitate the accumulation of biomass, influence redox homeostasis, and also mediate metabolic crosstalk with other cell types within the tumour microenvironment. This Review explores the roles of membrane transporters in physiological and malignant settings, and how these roles can affect drug response, through either indirect modulation of sensitivity or the direct transport of small-molecule therapeutic compounds into cells.

Keywords: Cancer Metabolism; Drug Uptake; Pharmacology; Transporters.

Fig. 1.

Types of SLC-mediated transport. Examples of plasma membrane SLC transporter types, showing their substrates and mechanisms of transport. The Na⁺/K⁺ ATPase pump (right) is an example of an active transporter that generates a Na⁺ gradient across the plasma membrane. This gradient drives the movement of Na⁺ ions and nucleosides via SLC28A1, making this SLC a secondary active transporter. SLC29A1, by contrast, is a facilitative uniporter that enables passage of nucleosides across the membrane dependent on their concentration gradient. SLC7A11 is an example of an antiporter and uses export of glutamate to drive the influx of cystine, the oxidised form of cysteine. The transporters are colour-coded based on their main substrate (see legend to Fig. 2 for details).

Fig. 2.

Genetic diversity of human SLCs and transcriptional heterogeneity of transporters in cancer. (A) A list of the SLC superfamily members was obtained from the HGNC website (https://www.genenames.org/data/genegroup/#!/group/752). As of December 2022, the superfamily contains 433 SLC transporters. Reviewed sequences were aligned using ClustalW in the R package msa, and the alignment was converted to a tree and visualised using the R packages ape and ggtree, respectively. Transporter families have been colour-coded according to substrate class, except for the mitochondrial transporters that, for evolutionary reasons, cluster together despite differential substrate preferences. (B) Dimensionality reduction analysis (using the UMAP package in R, with default settings) of patient samples from the TCGA database, based on the expression of SLC and ABC transporters. The transporter expression signatures in tumours are far more diverse (samples in blue, more dispersed) than in their matched normal tissue controls (samples in red, tightly clustered) across cancer types. This illustrates the heterogeneous expression of transporters in cancer. BRCA, breast-invasive carcinoma; COAD, colon adenocarcinoma; ESCA, oesophageal carcinoma; GBM, glioblastoma multiforme; LGG, brain low-grade glioma; LIHC, liver hepatocellular carcinoma; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; PAAD, pancreatic adenocarcinoma; PRAD, prostate adenocarcinoma; READ, rectum adenocarcinoma; SKCM, skin cutaneous melanoma.

Fig. 3.

Implications of transporter-dependent drug uptake for drug efficacy. (A) Examples of SLC-dependent drug entry into target cells. A broad range of SLCs facilitate the entry of a chemically diverse spectrum of compounds. Members of the SLC21, SLC22 and SLC47 families are well-known drug transporters. Beyond these, several emerging SLCs, including those illustrated, are becoming recognised for their capacity to import drugs. The latter range from anti-metabolites, such as methotrexate (Murakami and Mori, 2012) and gemcitabine, to small-molecule inhibitors of metabolic enzymes, exemplified by MOG, a rapidly formed degradation product of the prolylhydroxylase inhibitor DMOG, and enzyme-interacting proteins, such as the survivin inhibitor YM155. The transporters are colour-coded based on their main substrate (see legend to Fig. 2 for details). (B) The intracellular concentration of a drug depends on the expression level of the transporter, which affects target engagement and, consequently, the therapeutic efficacy of the drug.

Fig. 4.

Infographic to illustrate how transporters are co-opted in cancer.