Elsevier

Life Sciences

Volume 279, 15 August 2021, 119709
Life Sciences

Role of monocarboxylate transporters in head and neck squamous cell carcinoma

https://doi.org/10.1016/j.lfs.2021.119709Get rights and content

Abstract

Head and Neck tumors are metabolically highly altered solid tumors. Head and Neck cancer cells may utilise different metabolic pathways for energy production. Whereas, glycolysis is the major source coupled with oxidative phosphorylation in a metabolic symbiosis manner that results in the proliferation and metastasis in Head and Neck Cancer. The monocarboxylate transporters (MCTs) constitute a family of 14 members among which MCT1–4 are responsible for transporting monocarboxylates such as l-lactate and pyruvate, and ketone bodies across the plasma membrane. Additionally, MCTs mediate absorption and distribution of monocarboxylates across the cell membrane. Head and Neck cancer cells are highly glycolytic in nature and generate significant amount of lactic acid in the extracellular environment. In such condition, MCTs play a critical role in the regulation of pH, and lactate shuttle maintenance. The intracellular lactate accumulation is harmful for the cells since it drastically lowers the intracellular pH. MCTs facilitate the export of lactate out of the cell. The lactate export mediated by MCTs is crucial for the cancer cells survival. Therefore, targeting MCTs is important and could be a potential therapeutic approach to control growth of the tumor.

Introduction

Monocarboxylate transporters (MCTs) are encoded by SLC16A gene family and constitute a family of total 14 transmembrane proteins [1]. According to the Milton Saier transporter classification system, MCTs belong to the major facilitator superfamily (MFS) family [2]. In all the eukaryotic organisms, MCTs have been identified, of which the genomes have been sequenced to date. MCTs can transport wide variety of substrates such as lactate, pyruvate, ketone bodies, carnitine, aromatic and amino acids etc [3]. Of these identified 14 members of SLC16A1 gene family, the proton-coupled isoforms (MCT1-4) i.e. MCT1/SLC16A1, MCT2/SLC16A7, MCT3/SLC16A8 and MCT4/SLC16A3 are responsible in the metabolic process due to their roles in proton-linked transport of monocarboxylates such as pyruvate, l-lactate, and ketone bodies (d-β-hydroxybutyrate and acetoacetate). These passive transporters are localized primarily at the plasma membrane where they have the ability to operate in a bidirectional manner depending on the substrates concentration gradient [4]. MCT8/SLC16A2, is another best characterised MCT that has high affinity for T3 and T4 thyroid hormones [5], and MCT10/SLC16A10, aromatic amino acids transporter [6]. Studies have reported that MCT6 is crucial for the transport of bumetanide, used for the treatment of high blood pressure and edema [7]. In hepatocytes, MCT7/SLC16A6 is responsible for the export of ketone bodies [8]. In zebrafishes, loss of the MCT7 expression resulted in a condition known as hepatic steatosis (fatty liver). The condition was reversed by human MCT7 introduction in zebrafishes. MCT9/SLC16A9 has been identified as a transporter of pH-independent efflux of carnitine and sodium [9]. The functions and substrates of the other five MCT family member is currently unknown. The function of MCTs as monocarboxylates transporters is critical for the metabolic rewiring of stromal cells and tumor cells [10]. In order to rapidly generate ATP and lactate, cancer cells exhibit a metabolic shift from oxidative phosphorylation (OXPHOS) to glycolysis [11]. The lactate export mediated by MCTs is crucial for the survival of cancer cells (Table 1) [12].

The overexpression of MCTs (MCT1-4) have been reported in multiple cancers including Head and Neck squamous cell carcinoma (HNSCC), prostate cancer, peritoneal carcinomatosis, and lymphoma making them potentially active targets and biomarkers against a wide variety of cancers [12]. HNSCC tumors exhibit highly glycolytic phenotype, which produces significant amount of lactic acid. This results in the acidic tumor microenvironment [13]. In the cell, upregulated levels of lactate dehydrogenase (LDH) results in intracellular lactate accumulation. This causes increase in the intracellular pH of the cell and therefore is deleterious to the cancer cells [14]. In order to avoid this situation, MCTs facilitate lactate export out of the cell into the extracellular space. This causes HNSCC cells to balance their levels of intracellular pH [15]. Moreover, HNSCC tumors exist within a complex network of microenvironment, surrounded by stromal cells majorly endothelial cells, immune cells, and fibroblasts [16]. The metabolic interplay between these stromal cells and tumor cells provides advantages for tumor progression and proliferation [17]. Therefore, this review mainly addresses the role of MCTs in HNSCC and their therapeutic approaches to control the tumor growth, proliferation and metastasis.

Section snippets

Structure of MCT

As determined by the hydropathy plots, MCTs are anticipated to have 12 transmembrane (TM) α-helices with intracellular C-terminal and N-terminal and a large loop in the intracellular direction between TM 6 and TM 7 [4]. MCTs share variability in the TM 6 and TM 7 intracellular loop and C-temini, but share the greatest conservation within the regions in terms of protein sequences (Fig. 1) [4]. The crystal structures for a S. fumaroxidans homologue of human MCT1/MCT4 was recently determined [18].

Physiological regulation of MCT expression in HNSCC

Human cancers often express MCTs at high level [9]. HNSCC tumors often display upregulated levels of MCTs [40]. Hypoxia can induce the gene expression for MCT1, MCT2, and MCT4 directly via the activation of Hypoxia inducible factor-1 (HIF-1) for MCT4, or indirectly for the other two MCT isoforms i.e. MCT1 and MCT2 [10]. The gene expression induced by hypoxia is regulated by both lactate and pyruvate, indicating that, lactate, stimulates the hyperglycolytic phenotype by providing a positive

Function of MCTs in HNSCC

As mentioned in (Table 2), MCTs are widely expressed in various types of tumors including HNSCC. This is not only limited to cancer cells but stromal cells as well. MCTs exert multiple activities in HNSCC, including metabolic signalling and alteration, metabolic changes, and cancer metastasis.

Inhibitors of MCT

A majority of compounds have been shown to inhibit MCTs in a non-specific manner, 4′ -diisothiocyano-2,2′-stilbenedisulphonate (DIDS) binds to lysine residue on MCT1 and MCT2 thereby mediating transporters inactivation, but not MCT4 (Fig. 6) [73]. Organomercurial compounds for example p-chloromercuribenzenesulphonate (pCMBS) disrupts the interaction of MCT-CD147, thereby interfering with the expression pattern and activity of MCT1, MCT3, and MCT4 (Fig. 6) [24]. Pharmacological interest to

Conclusion

In this review, we have summarized our understanding and current knowledge of MCTs, their role, expression and functions, and their therapeutic implications in different types of cancer including HNSCC. MCTs with the help of lactate, sustains commensalism and metabolic cooperation, along with pro-angiogenic and metabolic signalling alteration in cancer. High expression of MCTs has been shown to be associated with poor prognosis in Head and Neck Cancer patients. For therapeutic purpose,

Funding source

Partially supported by Science and Engineering Research Board (SERB), Department of Science and Technology (DST), Government of India (ECR/2016/001489).

Declaration of competing interest

Authors declare no conflict of interest.

Acknowledgement

We thank you all authors for carefully reading the manuscripts and providing their valuable inputs.

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