You may have heard that cancer is a genetic disease, and that is true for many types of cancers. There are many known gene mutations in important genes that lead to different types of cancers. Similarly, many useful cancer models are generated by overexpressing an oncogene or deleting a tumor suppressor (Hanahan and Weinberg, 2011).
However, researchers recently found that making the interior of cells more basic is sufficient to initiate cancer, even in the absence of genetic perturbations (Grillo-Hill et al, 2015). Furthermore, drugs that restore normal pH levels work with other therapies to kill cancer cells and tumors in preclinical animal models of cancer (Cardone et al, 2015; Pilon-Thomas et al, 2016). These results indicate that pH is important for cancer, and it will be interesting to see whether similar approaches to reestablish normal pH in cells will successfully translate to human therapies.
The intracellular pH of cancer cells is slightly basic (7.3 – 7.6) whereas the extracellular pH is more acidic (6.8 – 7.0) (White et al, 2017). Altered pH enables cancer progression through altered metabolism, enhanced cell migration, enhanced growth signaling, and reduced sensitivity to cell death signaling.
These changes in cellular behavior are mediated by pH switches, or proteins that have altered activity, interactions, and stability, including the examples described below. In this article we will cover how slight changes in pH transform protein charge and function, and collectively drive disease progression.
Article Contents
Protein pH Switches
Changes in environmental pH are sensed by proteins by altering the charge on some ionizable amino acids. At the protein level there can be many outcomes from pH-mediated changes in charge including:
- Tuning enzymatic activities (Johnson et al, 2000; Matsuyama et al, 2000)
- Modulating protein oligomerization states (Currie et al, 2023; Politi et al, 2009)
- Altering protein stability (Chiariello et al, 2023; White et al, 2018)
- Influencing interactions with other biomolecules (White et al, 2018; Yao et al, 2020)
Figure 1. pH
influences protein activity, oligomerization, interactions, and stability. Note
that these parameters are not mutually exclusive – altered pH impacts b-catenin interactions and stability, for
example.
Note that these changes are not mutually exclusive, and often involve a change in the protein’s conformation. For example, pH regulates the interaction of b-catenin with another protein, which influences its stability, as we will cover in more detail below.
Evading Apoptosis
The first two pH-regulated proteins we will discuss are involved in the process of apoptosis. When it comes to cancer and cancer research, apoptosis or the lack of it plays a huge role.
Apoptosis is when a cell kills itself. While this might sound a bit dramatic and self-harming, apoptosis is a crucial process in normal development and homeostasis.
For example, during embryonic development our hands start off as continuous blocks of tissue with no spaces between our fingers. Developmentally-appropriate apoptosis removes that extra tissue so that we end up with individual fingers instead of webbed hands (Crocoll et al, 2002) (Figure 2).
Figure 2. The role of apoptosis in hand development.
Early in embryonic development our hands resemble clubs (left). Apoptosis of
tissues in between our digits or fingers (middle, magenta) makes it so we end
up with individual fingers (right) instead of webbed hands.
Did you know that our intestinal epithelium – the lining of cells between the intestinal lumen and the rest of our body – replaces itself every 3-4 days? New intestinal cells are being produced all this time to facilitate this turnover, and apoptosis plays a key role in clearing old intestinal cells to prevent a traffic jam of intestinal cells (Blander, 2016)!
A key point of both of these examples is that these cells are apoptosing at the right time and place in response to external cues. When our cells lose the ability to apoptose in the appropriate context, they grow unregulated, which is also known as cancer.
During apoptosis, cells cut up all of the biomolecules that they use to live and reproduce. We will discuss the pH regulation of caspases and DNAse II, which chop up protein and DNA molecules, respectively.
Caspases
Mitochondria are organelles that are crucial for apoptosis. They are normally more alkaline compared to the cytoplasm, and this difference becomes more dramatic during apoptosis. That is, when cells apoptose, the cytoplasm becomes more acidic and mitochondria more basic (Barry & Eastman, 1992).
When this change in pH happens, cytochrome C is released from mitochondria. Cytochrome C is a protein that is normally very important in a type of metabolism called oxidative phosphorylation, which we’ll talk a little more about in the metabolism section below. However, in the context of apoptosis, cytochrome C breaks free from mitochondria and stimulates caspases in the cytoplasm. The activated caspases then cut up other cellular proteins during apoptosis (Figure 3)(Matsuyama et al, 2000).
Figure 3. Partial apoptosis schematic. Upstream
signals trigger mitochondrial permeabilization (left), cytochrome C (small
orange circles) leaking out of mitochondrial leads to apoptosome formation
(middle), which triggers activation of downstream caspases that degrade
cellular proteins. Acidic pH promotes mitochondrial permeabilization and
apoptosome formation, and the basic pH of cancer cells downregulate these
functions and resulting apoptosis.
It turns out that cytosolic acidification is quite important for cytochrome C activating caspase activity. Cytochrome C oligomerizes with the protein Apaf-1 to form a beautiful molecular complex called the “apoptosome” (Figure 4). This spiral shaped scaffold stimulates caspase activation (Zhou et al, 2015). However, when the pH is maintained at neutral levels, cytochrome C does not stimulate caspases to cleave other proteins (Matsuyama et al, 2000).
Figure 4. Structure of the apoptosome (PDB: 3JBT). Cytochrome C (orange) binds to Apaf-1 (green) and stimulates its oligomerization. The apoptosome serves as a platform for activating caspases (Beem et al, 2004).
The more basic cytoplasm of cancer cells therefore disfavors apoptosis by limiting mitochondrial permeablilization and apoptosome formation (Figure 3). As you can see, the apoptosome is an elegant example of pH regulating both protein oligomerization and activity to affect cellular outcomes.
Deoxyribonuclease II
Deoxyribonuclease II, or DNAse II for short, is an enzyme that cuts DNA into little pieces in response to a variety of stimuli, including apoptosis (Figure 5). Cutting up DNA is a really important event in apoptosis because it ensures that the apoptosed cell cannot further replicate since it does not have any genetic material left to divide.
It’s important that once DNA degradation is initiated the job gets finished as it could be really deleterious to have cells with partial genomes replicating. In fact, the rare examples of cells with that kind of gross DNA alterations are cancer cells that have figured out a way to subvert apoptosis (Stephens et al, 2011).
DNAse II primarily resides within the lysosome, the acidic recycling center of the cell. Its activity is also highest at acidic pH ~ 5 which closely matches the lysosome pH of 4.7. Therefore, DNAse II is less active at the slightly more basic pH (7.3 -7.6) of tumor cells, thereby preventing apoptosis (Perez-Sala et al, 1995, White et al, 2017).
The internal pH is only adjusted a few tenths of a pH unit compared to normal cells, which seems like such a small difference. Remember, however, that pH is log scale so this change corresponds to a roughly two- to six-fold difference in H+ ion concentration – differences of this magnitude can make a big impact on biological systems (Phillips and Milo, 2009).
Figure 5 . DNAse II shown in surface representation
and colored blue for positive charge, and red for negative charge (PDB: 5I3E).
The active site that cleaves DNA is in the cleft of the U-shaped protein.
Since protein caspases and DNAse II are both stimulated at acidic pH, and inhibited at neutral pH, the alkalinization of tumor cells may be one strategy they use to prevent apoptosis (White et al, 2017).
Cellular Migration
An important hallmark of cancer cells is enhanced cellular migration (Hanahan and Weinberg, 2011). For solid tumors (meaning cancers other than leukemias or lymphomas) there is usually a primary tumor site where the cancer first grows. For example, the lung is the primary tumor site for lung cancer. However, this primary tumor is constantly shedding cancer cells which then moves to other sites in the body through a process called metastasis (Seyfried and Huysentruyt, 2013).
Metastasis is crucial in cancer etiology because most patients die due to metastases and not the actual primary tumor itself. For this reason, it is thought that successful methods for blocking metastasis would drastically reduce mortality rates for many types of cancer (Seyfried and Huysentruyt, 2013).
Cellular migration is fundamental to the metastatic process. From a cellular point of view, however, our bodies are a really crowded place making it difficult to move around. For an analogy in the easily observable world – let’s consider the Tokyo subway at rush hour. A cell trying to move through the body is like the last people trying to squeeze onto the Tokyo subway – it’s a tight fit!
Cancer cells upregulate proteins called matrix metalloproteases
(MMPs) to help them penetrate through the crowded body. MMPs cut up
extracellular proteins on other cells that otherwise would impede the cancer
cell’s migratory progress. To build on our image of the Tokyo subway, MMPs
would be like the subway pushers who shove people onto the subway in that they
enable movement through crowded environments.
Matrix metalloproteases are most active at a slightly acidic
pH of around 6 (Johnson et al, 2000). This means that MMPs will be more active
in the acidic extracellular pH of cancer cells. The enhanced activity is due to
a glutamate, Glu202, in the MMP active site that needs to be protonated for the
MMP to be active (Figure 6).
Glutamates normally have a pKa closer to 4, but in the case of MMPs the unique chemical environment of the active site modulates the pKa of Glu202 closer to 6 (Gomis-Ruth et al, 1997).
By the way, if you need a refresher on protein ionization and amino acid pKa values, this is a great article for that!
The expression of MMPs are also upregulated in cancer cells, so there are both more MMPs in cancer cells and they are more active in the tumor microenvironment compared to normal cells (Hollenhorst et al, 2011).
Metabolism
It has been known for roughly a century that cancer cells use a different type of metabolism than most other human cells. Cancer cells upregulate glucose import, and seemingly waste much of this glucose by inefficiently converting it into lactic acid. This shift in metabolism is often referred to as the “Warburg Effect” after Otto Warburg who first discovered these metabolic changes in cancer cells in the 1920s (Liberti & Locasale, 2016).
For a little background - in mammals, glucose is either converted into lactic acid or into carbon dioxide. Conversion of glucose to lactic acid is fast, but inefficient as it only generates two molecules of ATP per molecule of glucose. ATP is a fundamental unit of energy for cells that power the activity of many vital proteins.
In contrast, the full reduction of glucose to carbon dioxide through oxidative phosphorylation converts one molecule of glucose into 38 molecules of ATP – a seventeen fold increase in energy output! However, oxidative phosphorylation is much slower than lactic acid generation.
So why are tumor cells so metabolically so inefficient? There are a few thoughts on this subject, a couple of which deal with the tumor microenvironment.
The tumor microenvironment refers to the cancer cells that make up the tumor, as well as intertwined blood vessels, immune cells, and fibroblasts. In this crowded microenvironment there is fierce competition for resources such as glucose (Figure 7). Favoring the faster mode of metabolizing glucose into lactic acid may help tumor cells outcompete normal healthy cells for vital resources such as glucose (Chang et al, 2015).
Figure 7. Tumor cells (orange) are surrounded by
immune (blue), fibroblast (pink), and tissue specific (green) cells in the
crowded tumor microenvironment. Tumor cells secrete lactic acid (purple) to
prevent immune cells from activating and destroying them.
Upregulating lactic acid generation may help tumor cells outcompete immune cells in another, more direct manner. In ideal conditions, our immune system recognizes cancer cells and destroys them before we, or more importantly our oncologists, ever realize they are even there (Jaiswell et al, 2010)!
However, cancer cells use lactic acid to battle against the immune system. Lactic acid produced by cancer cells is excreted into the tumor microenvironment where it inhibits the ability of monocytes to mount an immune response against them. As the name suggests, lactic acid is acidic, and its inhibition of monocytes is in part due to the acidification of the tumor microenvironment conferred by lactic acid (Dietl et al, 2010).
So taken all together, cancer cells have altered metabolism to import more glucose, and generate and export more lactic acid. This, in turn, acidifies the extracellular environment which prevents our immune system from destroying the cancer cells (Figure 7).
Figure 8.
Lactic acid export prevents our immune system from destroying cancer cells.
Cancer cells upregulate glucose (orange hexagon) import. Cancer cells
downregulate oxidative phosphorylation (gray arrow) and upregulate lactic acid
(purple circles) production. Lactic acid is exported into the tumor
microenvironment, where it disrupts the ability of monocytes to activate our
immune system and destroy the cancer cells (Dietl et al, 2009). Lactic acid
inhibits monocyte activation, in part, by acidifying the tumor
microenvironment.
Escaping Degradation
b-catenin is a versatile protein with roles in both cell adhesion and gene expression. It’s also an oncogene that drives many different types of cancer – in fact around 10% of all cancers contain a b-catenin mutation (Forbes et al, 2017).
Since b-catenin is so important, the amount of this protein in healthy cells is tightly regulated. One mechanism for regulating the amount of b-catenin is through a class of proteins called E3 ubiquitin ligases. E3 ligases are like the garbage truck drivers of the cell; they go out and find proteins that need thrown away, and grab those proteins and carry them off to other proteins that do the actual degradation.
SCF is the name of the E3 ligase that binds to b-catenin and delivers it for degradation. There is a histidine residue, in b-catenin that is important for binding to SCF (Figure 9)(Wu et al, 2003). This histidine sits right in a positively-charged pocket on SCF. Histidine is an ionizable amino acid that can be either positive or neutral, depending on the surrounding pH.
Figure 9. b-catenin (orange) binding to SCF (PDB: 1P22). The surface of SCF is colored blue for positive charge and red for negative charge. A histidine residue (spheres) on b-catenin is important for binding to SCF. When the histidine is protonated, the positive charge prevents binding to SCF; when deprotonated the neutral charge accommodates binding to SCF.
It turns out, that in the pH of normal cells, this histidine is positively charged, which reduces its binding to the positive surface of SCF and stabilizes b-catenin (White et al., 2018). In contrast, the slightly more basic pH of cancer cells deprotonates this histidine residue leading to interaction with SCF and eventually b-catenin degradation (Figure 10).
Figure 10. SCF binds to b-catenin (left) then ubiquitinates b-catenin (middle), which marks it for degradation by the proteosome (right). Basic pH promotes interaction between SCF and b-catenin, and also b-catenin degradation through this mechanism.
But wait, if b-catenin drives cancer progression, why would it be degraded under the basic conditions of cancer cells? Remember those b-catenin mutations we talked about above? The most frequent site of mutation is in this region that binds to SCF, including the histidine residue (Forbes et al, 2017). These mutations prevent SCF interaction b-catenin, even under basic conditions, leading to an accumulation of this oncogene. One such mutation – histidine to arginine – functionally mimics the positive, protonated form of histidine to prevent SCF binding (Figure 11) (White et al, 2018).
Figure 11. The histidine residue on b-catenin is partially protonated at the pH
of normal cells, preventing interaction with SCF and downstream degradation of b-catenin (top left). At the more basic pH of
cancer cells the histidine becomes deprotonated and b-catenin binds to SCF leading to its degradation (top right).
The cancer-associated histidine to arginine mutations means that b-catenin does not bind to SCF and is not
degraded at either pH (bottom left and right). This mutation enables the
oncogene b-catenin to avoid degradation
in the more basic cancer cell pH.
So the b-catenin example is one where the switch to a more basic pH would actually inhibit a cancer-driving protein. That’s why the mutations that break this link and allow b-catenin to remain intact at basic intracellular pH of cancer cells appears to be critical in cancer progression. This is also an interesting example of pH-regulated interactions that impact protein stability.
In this article we have covered just a handful of the pH switches that are thought to contribute to cancer progression. Collectively, these changes contribute to tumorigenesis. Therefore, interventions that target cytosolic alkalinization may be useful cancer therapeutics, either individually or in combination with other targeted therapies (White et al, 2017).
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