Hypoxia restores the acidosis-induced inhibition of cancer cell dissemination.

Acidosis is a hallmark of the tumor microenvironment and has been linked to aggressive cancer behavior, characterized by increased migration, invasion, and metastasis. We herein demonstrate that short-term exposure (24-72 h) to acidic extracellular pH (pH(e) = 6.4) suppresses cell proliferation, metabolism, dissociation from tumor spheroids, and migration in vitro as well as extravasation in chick embryos and mice. Acidosis acutely inhibits motility by downregulating the activity of sodium-hydrogen exchanger isoform-1 (NHE1), which in turn suppresses phosphatidylinositol 3-kinase (PI3K)/Akt. PI3K/Akt inhibition blocks Yes-associated protein (YAP) translocation to the nucleus, reducing NHE1 and integrin-linked kinase (ILK) expression. The resulting reduction in NHE1-/ILK-dependent migration and ATP production is rescued by hypoxia across cell types. While certain cancer cells can adapt to long-term (>3 weeks) acidosis and acquire an aggressive phenotype, acidosis-induced adaptation is not universal and depends on the cell's ability to restrain reactive oxygen species overproduction via fatty acid oxidation.