Acid-adapted cancer cells alkalinize their cytoplasm by degrading the acid-loading membrane transporter Anion Exchanger 2 (SLC4A2)
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...
| Main Authors: | , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Cell Press
2023
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| _version_ | 1797110573952925696 |
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| author | Michl, J Monterisi, S White, B Blaszczak, W Hulikova, A Abdullayeva, G Bridges, E Yin, Z Bodmer, W Swietach, P |
| author_facet | Michl, J Monterisi, S White, B Blaszczak, W Hulikova, A Abdullayeva, G Bridges, E Yin, Z Bodmer, W Swietach, P |
| author_sort | Michl, J |
| collection | OXFORD |
| description | 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 relationships 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. |
| first_indexed | 2024-03-07T07:56:42Z |
| format | Journal article |
| id | oxford-uuid:e44e11c7-95a2-433d-883f-835c5b8fbd90 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:56:42Z |
| publishDate | 2023 |
| publisher | Cell Press |
| record_format | dspace |
| spelling | oxford-uuid:e44e11c7-95a2-433d-883f-835c5b8fbd902023-08-22T10:18:53ZAcid-adapted cancer cells alkalinize their cytoplasm by degrading the acid-loading membrane transporter Anion Exchanger 2 (SLC4A2)Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:e44e11c7-95a2-433d-883f-835c5b8fbd90EnglishSymplectic ElementsCell Press2023Michl, JMonterisi, SWhite, BBlaszczak, WHulikova, AAbdullayeva, GBridges, EYin, ZBodmer, WSwietach, PAcidic 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 relationships 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. |
| spellingShingle | Michl, J Monterisi, S White, B Blaszczak, W Hulikova, A Abdullayeva, G Bridges, E Yin, Z Bodmer, W Swietach, P Acid-adapted cancer cells alkalinize their cytoplasm by degrading the acid-loading membrane transporter Anion Exchanger 2 (SLC4A2) |
| title | Acid-adapted cancer cells alkalinize their cytoplasm by degrading the acid-loading membrane transporter Anion Exchanger 2 (SLC4A2) |
| title_full | Acid-adapted cancer cells alkalinize their cytoplasm by degrading the acid-loading membrane transporter Anion Exchanger 2 (SLC4A2) |
| title_fullStr | Acid-adapted cancer cells alkalinize their cytoplasm by degrading the acid-loading membrane transporter Anion Exchanger 2 (SLC4A2) |
| title_full_unstemmed | Acid-adapted cancer cells alkalinize their cytoplasm by degrading the acid-loading membrane transporter Anion Exchanger 2 (SLC4A2) |
| title_short | Acid-adapted cancer cells alkalinize their cytoplasm by degrading the acid-loading membrane transporter Anion Exchanger 2 (SLC4A2) |
| title_sort | acid adapted cancer cells alkalinize their cytoplasm by degrading the acid loading membrane transporter anion exchanger 2 slc4a2 |
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