Severe hypoxia increases expression of ATM and DNA-PKcs and it increases their activities through Src and AMPK signaling pathways

Highlights: • Severe hypoxia increased expression and activities of ATM and DNA-PKcs. • Severe hypoxia increased expression and activities of Src, EGFR, PDK1, and Akt. • A Src inhibitor PP2 suppressed activation of ATM and DNA-PKcs under sever hypoxia. • Severe hypoxia increased expression and activities of AMPKα. • Knockdown of AMPKα suppressed activities of ATM and DNA-PKcs and expression of ATM. Solid tumors often contain hypoxic regions because an abnormal and inefficient tumor vasculature is unable to supply sufficient oxygen. Tissue hypoxia is generally defined as a low oxygen concentration of less than 2%. It is well known that tumor cells under severe hypoxia, where oxygen concentration is less than 0.1%, show radioresistance. It has been reported that cells under severe hypoxia show different responses from those under mild hypoxia, where oxygen concentration is 0.5–2.0%. In the present study, we investigated the effects of severe hypoxia on expression and activities of ATM and DNA-dependent protein kinase catalytic subunit (DNA-PKcs), both of which regulate DNA double-strand breaks (DSBs) repair and radiation sensitivity. Signaling pathways for increasing expression and activities of ATM and DNA-PKcs under severe hypoxia were also investigated.