Radiotherapy in combination with hyperthermia suppresses lung cancer progression via increased NR4A3 and KLF11 expression

Purpose: Hyperthermia (HT), a clinical treatment involving delivery of heat to tumors, has been used in combination with traditional chemotherapy and radiotherapy to enhance their effects. However, the molecular mechanism underlying the high efficacy of combination therapy is not clear. This study was conducted to identify the molecular mechanism underlying the sensitization of lung cancer to radiotherapy by HT.

Materials and methods: Nuclear receptor subfamily 4, group A, member 3 (NR4A3) and Krüppel-like factor 11 (KLF11) expression in non-small-cell lung cancer cells was confirmed by performing real-time quantitative reverse transcription–polymerase chain reaction. Tumor cell proliferation and apoptosis were assessed via a colony-forming assay and Annexin V/propidium iodide staining.

Results and conclusions: Expression profile analysis revealed elevated levels of NR4A3 and KLF11 in A549 lung cancer cells after treatment with HT combined with radiation. We also confirmed that NR4A3 and KLF11 induced apoptosis and inhibited cell proliferation by elevating intracellular reactive oxygen species levels. Knockdown of NR4A3 or KLF11 using siRNA led to decreased effects of radiohyperthermia. Finally, the effect of these two factors on lung cancer progression was evaluated by in vivo xenograft studies. Taken together, the results suggest that NR4A3 and KLF11 are critical for increasing the efficacy of radiotherapy in combination with HT.