Elsevier

Cancer Treatment Reviews

Volume 29, Issue 6, December 2003, Pages 541-549
Cancer Treatment Reviews

LABORATORY–CLINIC INTERFACE
Cellular pH regulators: potentially promising molecular targets for cancer chemotherapy

https://doi.org/10.1016/S0305-7372(03)00106-3Get rights and content

Abstract

One of the major obstacles to the successful treatment of cancer is the complex biology of solid tumour development. Although regulation of intracellular pH has been shown to be critically important for many cellular functions, pH regulation has not been fully investigated in the field of cancer. It has, however, been shown that cellular pH is crucial for biological functions such as cell proliferation, invasion and metastasis, drug resistance and apoptosis. Hypoxic conditions are often observed during the development of solid tumours and lead to intracellular and extracellular acidosis. Cellular acidosis has been shown to be a trigger in the early phase of apoptosis and leads to activation of endonucleases inducing DNA fragmentation. To avoid intracellular acidification under such conditions, pH regulators are thought to be up-regulated in tumour cells. Four major types of pH regulator have been identified: the proton pump, the sodium–proton exchanger family (NHE), the bicarbonate transporter family (BCT) and the monocarboxylate transporter family (MCT). Here, we describe the structure and function of pH regulators expressed in tumour tissue. Understanding pH regulation in tumour cells may provide new ways of inducing tumour-specific apoptosis, thus aiding cancer chemotherapy.

Section snippets

Solid tumour growth and pH

In order to overcome cancer, it is important that we gain an understanding of the molecular mechanisms involved in the growth of solid tumours. In general, tumour cells up-regulate glycolysis and grow in a hypoxic microenvironment. Highly proliferative cancer cells produce a large amount of metabolic acid generated by glycolysis, glucose utilization and lactic acid production and increase proton efflux, thus preventing apoptosis by cellular acidosis (1). Figure 1 shows the complex pathways

Proton pump

The vacuolar proton pump (V-ATPase) belongs to a class of pumps that includes the F-ATPase (energy-coupling factors). The V-ATPase is composed of two multi-subunit sectors, the V0 and V1 domains, as shown in Figure 2. Table 1 shows the molecular mass, subunit function and human genes encoding each subunit. The V-ATPase is expressed in eukaryotes from yeast to man (9). It is present not only in the membrane of organelles, but also in the plasma membrane. The V-ATPase pumps protons from the

Sodium/proton exchanger

Proton fluxes across plasma membranes are regulated by several families of ion exchangers, including the sodium/proton exchanger (NHE). Seven NHE family members have been identified, as shown in Table 4. In humans, NHEs are comprised of 669–896 amino acids and are predicted to consist of 12 trans-membrane segments with cytoplasmic N- and C-terminal domains, Figure 3. The cytoplasmic domain of an NHE contains the pH sensor and maintenance sites. Among this family, NHE1 is ubiquitously expressed

Bicarbonate transporters

The mammalian bicarbonate transporter (BCT) superfamily is categorized into two families: (i) family members of the solute carrier 4 (SLC4), such as sodium bicarbonate co-transporters (NBCs 1–4) (47), sodium-dependent Cl/HCO3 exchanger (NCBE) and anion exchangers (AE 1–4), and (ii) some family members of the solute carrier 26 (SLC26). Table 5 summarizes the BCT families and their tissue distribution. NBCs are comprised of 1018–1137 amino acids and are predicted to consist of 12 trans-membrane

Monocarboxylate transporters

MCT play a central role in cellular metabolism (51) and are essential for transport monocarboxylates, such as lactate, across the plasma membrane. Several MCTs have been cloned and are known to belong to a new transporter family. Table 6 summarizes the chromosome localization and tissue distribution of the human MCT family. The predicted topology indicates that the number of trans-membrane domains is 12 with the N- and C-termini located within the cytoplasm, Figure 3. The trans-membrane helix

Prospects

In general, intracellular pH is similar in both solid tumour and normal tissues. However, extracellular pH is higher in normal tissue and lower in solid tumours. Thus there is a difference in the cellular pH gradient between the two tissues. The expression profile of pH regulators is also different in tumour and normal tissues. It has been shown that intracellular accumulation of various lipophilic anticancer agents is modulated by the cellular pH gradient. Thus, this difference in pH gradients

Acknowledgements

We thank Ms. Satoko Takazaki and Ms. Tokie Kawano for editorial help. This work was supported by the Ministry of Education, Culture, Sports, Science and Technology of Japan, by an ASTRA ZENECA Research Grant 2002 and by the Japan Medical Association.

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