Low dose radiation induces new protein synthesis that promotes cancer radiotherapy resistance

Radiotherapy (RT) is a cornerstone of cancer treatment; however, its efficacy is frequently hampered by its adverse effects on normal tissues. By studying the effects of high-dose radiotherapy (HDRT) and low-dose radiotherapy (LDRT), we found that cancer cells adapt distinct responses to these doses to reduce cytotoxicity. Upon HDRT, cancThese authors contributed equally to this worker cells initiate a strong DNA damage response (DDR) to gain resistance through rapid production and/or activation of proteins for cell cycle arrest and DNA damage repair. In contrast, LDRT has a milder effect on the DDR and promotes resistance by triggering the synthesis of new proteins, including those essential for DNA repair and protein damage clearance. We showed that the inhibition of proteasome activity using a proteasome inhibitor (PI) result in the accumulation of damage to both proteins and DNA, leading to the profound death of cancer cells. Mechanistically, LDRT enhances protein synthesis through both increased mTOR signaling and 80S ribosome assembly. On the basis of these findings, we designed a chemoradiotherapy strategy that combines LDTR with PI to treat cancer while minimizing non-targeted toxicity.