Fig. 9.

A simplified diagram of putative signaling pathways accountable for the differential responses of MO59K (a, c) and MO59J (b, d) cells to DNA-PK/PI3K/mTOR-inhibition and IR. Irradiation of MO59K cells in the presence of PI-103 showed increased radiation sensitivity (c) compared with the irradiated drug-free controls (a). Intrinsically radiosensitive MO59J cell line (b) is characterized by the absence of DNA-PK, and deficiencies in ATM and in NHEJ-repair. Both DNA-PK and ATM redundantly phosphorylate similar substrates, e.g. both are required for normal levels of p53 phosphorylation and p53-dependent apoptosis [37]. Accordingly, we found diminished expression of p53 in MO59J cells, which was further reduced in the presence of PI-103. Subsequently, the reduction of p53 might impede two most prominent outcomes of p53 function, i.e. cell-cycle arrest and apoptosis. Indeed, PI-103-treated and irradiated MO59J cells showed less apoptosis, reduced G2-arrest, increased S-phase fraction and cytoprotective authophagy compared with the irradiated drug-free MO59J cells (b). The findings might explain PI-103-induced radioresistance in MO59J cells (d) compared with the irradiated drug-free controls (b). (Note the size of the letters/symbols and the thickness of the lines, indicating expression levels). For details, see text