5 research outputs found

    Normoxic cells remotely regulate the acid-base balance of cells at the hypoxic core of connexin-coupled tumor-growths

    No full text
    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

    Normoxic cells remotely regulate the acid-base balance of cells at the hypoxic core of connexin-coupled tumor-growths

    No full text
    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

    The enhancement of glycolysis regulates pancreatic cancer metastasis

    No full text
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