Water induces autocrine stimulation of tumor cell killing through ATP release and P2 receptor binding.
Although exposure of cells to extreme hypotonic stress appears to be a purely experimental set up, it has found an application in clinical routine. For years, surgeons have washed the abdominal cavity with distilled water to lyse isolated cancer cells left after surgery. No data are available supporting this practice or evaluating the potential mechanisms of cell injury under these circumstances. Recent evidence indicates that increases in cell volume stimulate release of adenosine triphosphate and autocrine stimulation of purinergic (P2) receptors in the plasma membrane of certain epithelial cell types. Under physiological conditions, purigenic stimulation can contribute to cell volume recovery through activation of solute efflux. In addition, adenosine triphosphate-P2 receptor binding might trigger other mechanisms affecting cell viability after profound hypotonic stress. This study demonstrates a novel pathway of cell death by apoptosis in human colon cancer cells following a short hypotonic stress. This pathway is induced by transitory cell swelling which leads to extracellular release of adenosine triphosphate (ATP) and specific binding of ATP to P2 receptors (probably P2X7). Extracellular ATP induced activation of caspases 3 and 8, annexin V, release of cytochrome c, and eventually cell death. The effect of ATP can be blocked by addition of (i) apyrase to hydrolyse extracellular ATP and (ii) suramin, a P2 receptor antagonist. Finally, (iii) gadolinium pretreatment, a blocker of ATP release, reduces sensitivity of the cells to hypotonic stress. The adenosine triphosphate-P2 receptor cell death pathway suggests that autocrine/paracrine signaling may contribute to regulation of viability in certain cancer cells disclosed with this pathway.
Department of Visceral and Transplantation Surgery, Zurich University Hospital, Zurich, Switzerland.
N
N
Selzner
M
M
Selzner
R
R
Graf
U
U
Ungethuem
J G
JG
Fitz
P-A
PA
Clavien
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007038:Hypotonic Solutions / Q000494:pharmacology; D008928:Mitochondria / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D018048:Receptors, Purinergic P2 / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D058486:Receptors, Purinergic P2X7; D013997:Time Factors; D014867:Water / Q000494:pharmacology*
D007038:Hypotonic Solutions; C546468:P2RX7 protein, human; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D014867:Water; D000255:Adenosine Triphosphate; D020169:Caspases