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-κB) in contributing to acquired
cisplatin resistance in
HNSCC, the expression and activity of NF-κB and its upstream
kinases, IKKα and IKKβ, 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-κB p65 activity was elevated in
cisplatin resistant
HNSCC cells compared to that in their parent cells. Importantly, the phosphorylation of NF-κB p65 at
serine 536 and the phosphorylation of IKKα and IKKβ at their activation loops were dramatically elevated in the resistant cell lines. Furthermore, knockdown of NF-κB or overexpression of p65-S536
alanine (p65-S536A) mutant sensitizes resistant cells to
cisplatin. Additionally, the novel IKKβ inhibitor CmpdA has been shown to consistently block the phosphorylation of NF-κB 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-κB plays a pivotal role in controlling acquired
cisplatin resistance and that targeting the IKK/NF-κB signaling pathway may provide a possible therapeutic method to overcome the acquired resistance to
cisplatin in
HNSCC.