Acid-adapted cancer cells alkalinize their cytoplasm by degrading the acid-loading membrane transporter anion exchanger 2, SLC4A2
Johanna Michl,
Stefania Monterisi,
Bobby White,
Wiktoria Blaszczak,
Alzbeta Hulikova,
Gulnar Abdullayeva,
Esther Bridges,
Zinan Yin,
Walter F. Bodmer,
Pawel Swietach
Affiliations
Johanna Michl
Department of Physiology, Anatomy and Genetics, Parks Road, Oxford OX1 3PT, UK
Stefania Monterisi
Department of Physiology, Anatomy and Genetics, Parks Road, Oxford OX1 3PT, UK
Bobby White
Department of Physiology, Anatomy and Genetics, Parks Road, Oxford OX1 3PT, UK
Wiktoria Blaszczak
Department of Physiology, Anatomy and Genetics, Parks Road, Oxford OX1 3PT, UK
Alzbeta Hulikova
Department of Physiology, Anatomy and Genetics, Parks Road, Oxford OX1 3PT, UK
Gulnar Abdullayeva
MRC Weatherall Institute for Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK
Esther Bridges
Department of NDM Experimental Medicine, MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, JR Hospital, Headington, Oxford OX3 9DS, UK
Zinan Yin
Department of NDM Experimental Medicine, MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, JR Hospital, Headington, Oxford OX3 9DS, UK
Walter F. Bodmer
MRC Weatherall Institute for Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK
Pawel Swietach
Department of Physiology, Anatomy and Genetics, Parks Road, Oxford OX1 3PT, UK; Corresponding author
Summary: Acidic environments reduce the intracellular pH (pHi) of most cells to levels that are sub-optimal for growth and cellular functions. Yet, cancers maintain an alkaline cytoplasm despite low extracellular pH (pHe). Raised pHi is thought to be beneficial for tumor progression and invasiveness. However, the transport mechanisms underpinning this adaptation have not been studied systematically. Here, we characterize the pHe-pHi relationship in 66 colorectal cancer cell lines and identify the acid-loading anion exchanger 2 (AE2, SLC4A2) as a regulator of resting pHi. Cells adapt to chronic extracellular acidosis by degrading AE2 protein, which raises pHi and reduces acid sensitivity of growth. Acidity inhibits mTOR signaling, which stimulates lysosomal function and AE2 degradation, a process reversed by bafilomycin A1. We identify AE2 degradation as a mechanism for maintaining a conducive pHi in tumors. As an adaptive mechanism, inhibiting lysosomal degradation of AE2 is a potential therapeutic target.
