Normoxic cells remotely regulate the acid-base balance of cells at the hypoxic core of connexin-coupled tumor-growths
A significant proportion of ATP fuels the removal of metabolic end-products, particularly H+ ions which profoundly affect biological activities. Since energetic resources in hypoxic tumor-regions are constrained by low-yielding glycolysis, any means of reducing the cost of acid-extrusion, without co...
| Asıl Yazarlar: | , , , , |
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| Materyal Türü: | Journal article |
| Baskı/Yayın Bilgisi: |
Federation of American Society of Experimental Biology
2017
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| _version_ | 1826283779469082624 |
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| author | Dovmark, TH Hulikova, A Niederer, SA Vaughan-Jones, RD Swietach, P |
| author_facet | Dovmark, TH Hulikova, A Niederer, SA Vaughan-Jones, RD Swietach, P |
| author_sort | Dovmark, TH |
| collection | OXFORD |
| description | A significant proportion of ATP fuels the removal of metabolic end-products, particularly H+ ions which profoundly affect biological activities. Since energetic resources in hypoxic tumor-regions are constrained by low-yielding glycolysis, any means of reducing the cost of acid-extrusion, without compromising pH homeostasis, would be advantageous. Some cancers express connexin channels for allowing solute exchange, and we propose that, via this route, normoxic cells supply hypoxic neighbors with acid-neutralizing HCO3 − ions. This was tested by imaging cytoplasmic pH in spheroidal tissue-growths of connexin43-positive pancreatic cancer Colo357 cells during light-controlled H+ -uncaging at the hypoxic core. Acid-retention in hypoxic cells was halved in the presence of CO2/HCO3 − , but requires a restorative flux of HCO3 − ions. The effect of CO2/HCO3 − was ablated by connexin43 inhibition or knockdown. In connexin-decoupled spheroids, DIDS, an inhibitor of extracellular HCO3 − uptake, had no effect on cytoplasmic [H+ ] in the H+ -uncaging region, indicating that DIDS-sensitive transport is not an adequate pH-regulatory strategy at the hypoxic core. Under functional connexin-coupling, acid-retention in hypoxic cells increased with DIDS, indicating that HCO3 − ions are taken-up actively by peripheral cells and then transmitted passively to hypoxic cells. Thus, the energetic burden of pH regulation is off-loaded from hypoxic cells onto metabolically-altruistic normoxic neighbors. |
| first_indexed | 2024-03-07T01:04:02Z |
| format | Journal article |
| id | oxford-uuid:8ab6f615-6824-4a6c-8c98-8c04185ea58c |
| institution | University of Oxford |
| last_indexed | 2024-03-07T01:04:02Z |
| publishDate | 2017 |
| publisher | Federation of American Society of Experimental Biology |
| record_format | dspace |
| spelling | oxford-uuid:8ab6f615-6824-4a6c-8c98-8c04185ea58c2022-03-26T22:33:16ZNormoxic cells remotely regulate the acid-base balance of cells at the hypoxic core of connexin-coupled tumor-growthsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:8ab6f615-6824-4a6c-8c98-8c04185ea58cSymplectic Elements at OxfordFederation of American Society of Experimental Biology2017Dovmark, THHulikova, ANiederer, SAVaughan-Jones, RDSwietach, PA significant proportion of ATP fuels the removal of metabolic end-products, particularly H+ ions which profoundly affect biological activities. Since energetic resources in hypoxic tumor-regions are constrained by low-yielding glycolysis, any means of reducing the cost of acid-extrusion, without compromising pH homeostasis, would be advantageous. Some cancers express connexin channels for allowing solute exchange, and we propose that, via this route, normoxic cells supply hypoxic neighbors with acid-neutralizing HCO3 − ions. This was tested by imaging cytoplasmic pH in spheroidal tissue-growths of connexin43-positive pancreatic cancer Colo357 cells during light-controlled H+ -uncaging at the hypoxic core. Acid-retention in hypoxic cells was halved in the presence of CO2/HCO3 − , but requires a restorative flux of HCO3 − ions. The effect of CO2/HCO3 − was ablated by connexin43 inhibition or knockdown. In connexin-decoupled spheroids, DIDS, an inhibitor of extracellular HCO3 − uptake, had no effect on cytoplasmic [H+ ] in the H+ -uncaging region, indicating that DIDS-sensitive transport is not an adequate pH-regulatory strategy at the hypoxic core. Under functional connexin-coupling, acid-retention in hypoxic cells increased with DIDS, indicating that HCO3 − ions are taken-up actively by peripheral cells and then transmitted passively to hypoxic cells. Thus, the energetic burden of pH regulation is off-loaded from hypoxic cells onto metabolically-altruistic normoxic neighbors. |
| spellingShingle | Dovmark, TH Hulikova, A Niederer, SA Vaughan-Jones, RD Swietach, P Normoxic cells remotely regulate the acid-base balance of cells at the hypoxic core of connexin-coupled tumor-growths |
| title | Normoxic cells remotely regulate the acid-base balance of cells at the hypoxic core of connexin-coupled tumor-growths |
| title_full | Normoxic cells remotely regulate the acid-base balance of cells at the hypoxic core of connexin-coupled tumor-growths |
| title_fullStr | Normoxic cells remotely regulate the acid-base balance of cells at the hypoxic core of connexin-coupled tumor-growths |
| title_full_unstemmed | Normoxic cells remotely regulate the acid-base balance of cells at the hypoxic core of connexin-coupled tumor-growths |
| title_short | Normoxic cells remotely regulate the acid-base balance of cells at the hypoxic core of connexin-coupled tumor-growths |
| title_sort | normoxic cells remotely regulate the acid base balance of cells at the hypoxic core of connexin coupled tumor growths |
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