LABORATORY–CLINIC INTERFACECellular pH regulators: potentially promising molecular targets for 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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