IKK phosphorylation of NF-κB at serine 536 contributes to acquired cisplatin resistance in head and neck squamous cell cancer.

Current treatment methods for advanced head and neck squamous cell carcinoma (HNSCC) include surgery, radiation therapy and chemotherapy. For recurrent and metastatic HNSCC, cisplatin is the most common treatment option, but most of patients will eventually develop cisplatin resistance. Therefore, it is imperative to define the mechanisms involved in cisplatin resistance and find novel therapeutic strategies to overcome this deadly disease. In order to determine the role of nuclear factor-kappa B (NF-kappa B) in contributing to acquired cisplatin resistance in HNSCC, the expression and activity of NF-kappa B and its upstream kinases, IKK alpha and IKK beta, were evaluated and compared in three pairs of cisplatin sensitive and resistant HNSCC cell lines, including a pair of patient derived HNSCC cell line. The experiments revealed that NF-kappa B p65 activity was elevated in cisplatin resistant HNSCC cells compared to that in their parent cells. Importantly, the phosphorylation of NF-kappa B p65 at serine 536 and the phosphorylation of IKKa and IKK beta at their activation loops were dramatically elevated in the resistant cell lines. Furthermore, knockdown of NF-kappa B or overexpression of p65-S536 alanine (p65-S536A) mutant sensitizes resistant cells to cisplatin. Additionally, the novel IKK beta inhibitor CmpdA has been shown to consistently block the phosphorylation of NF-kappa B at serine 536 while also dramatically improving the efficacy of cisplatin in inhibition of cell proliferation and induction of apoptosis in the cisplatin resistant cancer cells. These results indicated that IKK/NF-kappa B plays a pivotal role in controlling acquired cisplatin resistance and that targeting the IKK/NF-kappa B signaling pathway may provide a possible therapeutic method to overcome the acquired resistance to cisplatin in HNSCC.