Inhibition of IKK-NFκB pathway sensitizes lung cancer cell lines to radiation

Objective: Cancer cell radioresistance is a stumbling block in radiation therapy. The activity in the nuclear factor kappa B (NF kappa B) pathway correlates with anti-apoptotic mechanisms and increased radioresistance. The IKK complex plays a major role in NF kappa B activation upon numerous signals. In this study, we examined the interaction between ionizing radiation (IR) and different members of the IKK-NF kappa B pathway, as well as upstream activators, RAF1, ERK, and AKT1. Methods: The effect of 4 Gy of IR on the expression of the RAF1-ERK-IKK-NF kappa B pathway was examined in A549 and H1299 lung cancer cell lines using Western blot analysis and confocal microscopy. We examined changes in radiation sensitivity using gene silencing or pharmacological inhibitors of ERK and IKK beta. Results: IKK alpha, IKK gamma, and I kappa B alpha increased upon exposure to IR, thereby affecting nuclear levels of NF kappa B (phospho-p65). ERK inhibition or siRNA-mediated down-regulation of RAF1 suppressed the post-irradiation survival of the examined lung cancer cell lines. A similar effect was detected on survival upon silencing IKK alpha/IKK gamma or inhibiting IKK beta. Conclusions: Exposure of lung cancer cells to IR results in NF kappa B activation via IKK. The genetic or pharmacological blockage of the RAF1-ERK-IKK-NF kappa B pathway sensitizes cells to therapeutic doses of radiation. Therefore, the IKK pathway is a promising target for therapeutic intervention in combination with radiotherapy.