Journal
FASEB JOURNAL
Volume 32, Issue 1, Pages 83-96Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.201700480R
Keywords
homeostasis; gap junctions; bicarbonate transport; pancreatic cancer; metabolic altruism
Categories
Funding
- European Commission through IonTraC Marie Curie Initial Training Network FP7-PEOPLE-ITN [289648]
- Royal Society and Worldwide Cancer Research Grant [2012/0027]
- EPSRC [EP/M012492/1] Funding Source: UKRI
Ask authors/readers for more resources
ATP fuels the removal of metabolic end-products, including H+ ions that profoundly modulate biological activities. Energetic resources in hypoxic tumor regions are constrained by low-yielding glycolysis, and any means of reducing the cost of acid extrusion, without compromising pH homeostasis, would therefore be advantageous for cancer cells. Some cancers express connexin channels that allow solute exchange between cells, and we propose that, via this route, normoxic cells supply hypoxic neighbors with acid-neutralizing HCO3- ions. This hypothesis was tested by imaging cytoplasmic pH in spheroidal tissue growths of connexin43-positive pancreatic cancer Colo357 cellsduring light-controlled H+ uncaging at thehypoxic core. Cytoplasmic acid retention at the core was halved in the presence of CO2/HCO3-, but this process requires a restorative HCO3- flux. The effect of CO2/HCO3- was ablated by connexin43 inhibition or knockdown. In connexin-decoupled spheroids, 4,49-diisothiocyano-2,29-stilbenedisulfonic acid (DIDS), an inhibitor of 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 therein. With intact connexin-coupling, acid retention at the core increased upon DIDS treatment, indicating that HCO3- ions are taken up actively by peripheral cells and then transmitted passively to cells at the hypoxic core. Thus, the energetic burden of pH regulation is of floaded from hypoxic cells onto metabolically altruistic normoxic neighbors.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available