Non-small cell lung cancer (NSCLC) has a very poor prognosis even when treated with the best
therapies available today often including radiation. NSCLC is frequently complicated by pulmonary
infections which appear to impair prognosis as well as
therapy, whereby the underlying mechanisms are still not known. It was investigated here, whether the bacterial
lipopolysaccharides (LPS) might alter the
tumor cell radiosensitivity. LPS were found to induce a radioresistance but solely in cells with an active TLR-4 pathway.
Proteome profiling array revealed that LPS combined with irradiation resulted in a strong phosphorylation of
cAMP response element-binding protein (CREB). Inhibition of
CREB binding protein (CBP) by the specific inhibitor
ICG-001 not only abrogated the LPS-induced radioresistance but even led to an increase in radiosensitivity. The sensitization caused by
ICG-001 could be attributed to a reduction of
DNA double-strand break (
DSB) repair. It is shown that in NSCLC cells LPS leads to a CREB dependent radioresistance which is, however, reversible through CBP inhibition by the specific inhibitor
ICG-001. These findings indicate that the combined treatment with radiation and CBP inhibition may improve survival of NSCLC patients suffering from pulmonary
infections.