Figure 6.

Simplified schema of putative signaling pathways accountable for the differential responses of A549 (A) and SNB19 (B) cell lines to Hsp90 inhibition and IR. In A549 cells (A), the wild-type PTEN along with Hsp90 inhibition apparently suppress the PI3K/Akt pathway. As a consequence, the cells produce less the antiapoptotic protein Bcl-xL. In parallel, IR might activate the wild-type p53 in A549 cells, which in turn triggers the caspase-dependent apoptosis. As a result of Hsp90 inhibition, the expression of the Hsp90 client protein Cdk4 decreases in A549 cells, and through depleted pRB, it cause a G₁-phase arrest in the drug-treated and irradiated A549 cells. In contrast to A549 cells, the PTEN-null SNB19 cells (B) express constitutively elevated amounts of the antiapoptotic PI3K and Akt, which favor the survival and growth of this cell line. Besides this, p53 protein is mutated in SNB19 cells, which might be the reason for the lack of activation of caspase 9 (not detected) and subsequently of caspase 3. Moreover, the activated Akt in SNB19 cells, together with IR, induces almost twice as much ROS, which is indicative of DNA damage (about histone γH2AX), compared to that in A549 cells. In addition, SNB19 cells repair the IR-induced DNA damage much more slowly than do A549 cells. Finally, ROS also activate p21, which in turn inhibits Cdk1 in SNB19 cells, thus leading to a strong G₂/M arrest (for more details, see text). The schema was proposed using the data presented in Figures 1 to 5, W1 to W3, and W7 and Table W1. Note the size of the letters/symbols and the thickness of the lines; gray means strong reduction or depletion of proteins.