Effects of a TAK1 inhibitor on radiation-and heat-induced cell killing

Transforming growth factor-beta-activated kinase1 (TAK1) appears to play an anti-apoptotic role in response to multiple stresses and has been reported to be a responsive kinase that regulates cell survival in KRAS-dependent cells. In this study, we focused on the synergistic effects of 5Z-7-oxozeaenol, a TAK1 inhibitor, with hyperthermia (HT) in KRAS mutant lung cancer cell line A549 cells. Here, enhancement in apoptosis induced by HT exposure was observed, when the cells were pre-incubated with 5Z-7-oxozeaenol. The enhancement was accompanied by significant increase in reactive oxygen species generation and mitochondrial membrane potential loss. In addition, the drug promoted HT-induced expressions of cleaved caspase-3, cleaved caspase-8, HSP70 and decreased HT-induced expressions of Bcl-2, p-p38, p-JNK and LC3. Taken together, our data provides further insights of the mechanism of action of 5Z-7-oxozeaenol and HT treatmentfor patients with KRAS mutant lung cancer.