Hypoxia restores the acidosis-induced inhibition of cancer cell dissemination

TL;DR

Short-term acidosis reduces cancer cell aggression, but hypoxia can reverse this effect by restoring cell movement and energy balance.

Contribution

The study reveals how hypoxia counteracts acidosis-induced suppression of cancer cell motility and bioenergetics.

Findings

Short-term acidosis inhibits cancer cell migration and metastasis by suppressing NHE1 and PI3K/Akt signaling.

Hypoxia rescues acidosis-induced motility inhibition by restoring NHE1/ILK function and glycolysis.

Adaptation to chronic acidosis is cell-specific and depends on fatty acid oxidation to control ROS.

Abstract

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 (pHe = 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.

Lee et al. reveal that short-term acidosis suppresses cancer cell aggressiveness across cell types. Hypoxia overrides acidosis-mediated inhibition of motility by restoring NHE1/ILK function and maintaining bioenergetic balance through compensatory glycolysis. Adaptation to chronic acidosis is cell-specific and depends on a cell’s ability to restrain ROS via fatty acid oxidation.

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