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New research led by Dr Johanna Michl and Professor Pawel Swietach has solved the longstanding mystery of how cancer cells are able to maintain a relatively alkaline intracellular pH, despite being surrounded by an acidic environment. A raised intracellular pH is required for cancer progression because it allows cancer cells to efficiently proliferate and metastasise. However, until now the exact molecular mechanism underlying this adaptation was unknown.

Two side by side tissue samples from a human colon. On the left shows a sample from a  normal colon (more alkaline) and on the right shows colorectal cancer tissue, characterised by higher acidity.
Human tissue samples from normal tissue or colorectal cancer with AE2 (marker for alkaline regions) labelled in red, LAMP2 (marker for acidic regions) labelled in green and nuclei labelled in blue using DAPI. The figure highlights that AE2 levels are often reduced in tumour tissues, which are characterised by an acidic microenvironment.

Extracellular acidity is a common feature of many solid tumours, similar to hypoxia. Increased metabolic rates, higher glycolysis and inadequate vasculature all contribute to the accumulation of acid in the tumour microenvironment. Due to the coupling of intra- and extracellular pH, acidity is expected to decrease the pH of the cytoplasm. However, this is not the case in cancer cells and many previous studies have reported that cancer cells have a relatively alkaline intracellular pH. 

The study by Dr Johanna Michl and the Swietach Group team shows that chronic extracellular acidity triggers the degradation of the membrane transporter anion exchanger 2 (AE2, SLC4A2). Eliminating an important protein for loading acid into the cells leads to an increased intracellular pH, comparable to levels in normal cells. This acts as an important adaptation mechanism, and allows the cells to maintain their intracellular pH at physiological levels.

The team also show that chronic acidity inhibits the mTOR signalling pathway, which stimulates the function of lysosomes, a cellular compartment responsible for protein degradation. Following acid-treatment, lysosomes degrade AE2 protein, which raises intracellular pH. If lysosomal function is blocked during acid-treatment using chemical inhibitors (such as bafilomycin A1), AE2 protein levels can be restored. The reversal of AE2 degradation in acid-treated cells acidifies the cytoplasm, and triggers cell death. Therefore, inhibiting the lysosomal degradation of AE2 is a promising research avenue, with therapeutic potential for many types of cancer.

Dr Michl said: “We are thrilled to have discovered a critical mechanism explaining how cancer cells regulate their intracellular pH, a factor which can greatly influence cancer progression and aggressiveness. We have observed AE2 degradation as a mechanism to adapt to chronic acidity in several tumour types, and believe it is a universal phenomenon. Unfortunately, the tools for specifically preventing AE2 degradation, without interfering with the degradation of many other proteins are not yet available. However, inhibiting such a fundamental mechanism would have the potential to lessen the tumour burden and invasiveness of several cancer types.”

The full paper “Acid-adapted cancer cells alkalinize their cytoplasm by degrading the acid-loading membrane transporter anion exchanger2, SLC4A2” is available to read in Cell Reports volume 42, issue 6, June 27 2023.


Text credit to Dr Johanna Michl and Dr Wiktoria Blaszczak