PIM1‐activated PRAS40 Regulates Radioresistance in Non‐small Cell Lung Cancer Cells through Interplay with FOXO3a, 14‐3‐3, and Protein Phosphatases

Abstract

Resistance of cancer cells to ionizing radiation (IR) plays an important role in the clinical setting of lung cancer treatment. To date, however, the exact molecular mechanism of radiosensitivity has not been well explained. In this study, we compared radioresistance in two types of non‐small cell lung cancer (NSCLC) cells, NCI‐H460 and A549, and investigated the signaling pathways that confer radioresistance. In radioresistant cells, IR led to overexpression of PIM1 and reduction of protein phosphatases (PP2A and PP5), which induced translocation of PIM1 into nucleus. Increased nuclear PIM1 phosphorylated PRAS40. Consequently, pPRAS40 made a trimeric complex with 14‐3‐3 and AKT‐activated pFOXO3a, which then moved rapidly to cytoplasm. Cytoplasmic retention of FOXO3a was associated with down‐regulation of pro‐apoptotic genes and possibly radioresistance. On the other hand, a suppressive effect of IR on protein phosphatases was not detected and, concomitantly, protein phosphatases down‐regulated PIM1 in radiosensitive cells. In this setting, PIM1‐activated pPRAS40, AKT‐activated pFOXO3a, and their complex formation with 14‐3‐3 could be key regulators of the IR‐induced radioresistance in NSCLC cells.