Actin disruption inhibits hypoxia inducible factor-1α expression via inactivity of Mdm2-mediated p70S6K

The intracellular actin cytoskeleton is a central player in tumor cell migration and adhesion, and interacts with the extracellular matrix during the progression to metastasis. Although recent reports on motility events have revealed that the destabilization of actin affects cancer progression and hypoxia inducible factor-1 alpha (HIF-1 alpha) activity, little is known about the responsive activity of HIF-1 alpha following actin disruption. Here, we demonstrate that the inhibition of actin polymerization or depolymerization attenuates HIF-1 alpha expression independently of proteasomal degradation. The disruption of actin dynamics inactivates HIF-1 alpha translational expression through p70(S6K) translational signaling; this is independent of p53 activation, suggesting that actin dysfunction-mediated HIF-1 alpha destabilization may lead to the development of novel anticancer chemotherapeutic targets.