The role of the STAT3 signaling transduction pathways in radioresistance

The efficacy of radiotherapy has long known to be limited by the emergence of resistance. The four Rs of radiotherapy (DNA damage repair, reoxygenation, redistribution of the cell cycle, and repopulation) are generally accepted concepts in radiobioolgy. Recent studies have strongly linked signal transducer and activator of transcription 3 (STAT3) to the regulation of cancer stemness and radioresistance. In particular, a STAT3 pathway inhibitor napabucasin, claimed to be the first cancer stemness antagonist in clinical trials, strengthens the link. However, no reviews connect STAT3 with the four Rs of radiotherapy. Herein, the evidence-based role of STAT3 in radioresistance is discussed in relation to the four Rs of radiotherapy. The proposed mechanisms include upstream and downstream effector proteins of STAT3, including FOXM1, MELK, NEK2, AKT, EZH2, and HIF1α. Downstream transcriptional products of the mechanistically-related proteins are involved in cancer stemness, anti-apoptosis, and the four Rs of radiotherapy. Utilizing selective inhibitors of the mechanistically-related proteins has shown promising antagonism of radioresistance, suggesting that the expression levels of these proteins may be biomarkers for the prediction of radiotherapeutic outcomes, and that this molecular mechanism may provide a rational axis through which to treat radioresistance.