NF-kappa-B inhibitor alpha mediates cancer stemness characteristics in oral squamous cell carcinoma by interacting with cathepsin B.

The role of NF-kappa-B inhibitor alpha (IkappaBalpha), a well-established negative regulator of the NF-kappaB signalling pathway in cancer is complex, as evidenced by either promoting or suppressing tumourigenesis, depending on the cancer type, however, in oral squamous cell carcinoma (OSCC) remains unelucidated. Here, for the first time, we report that the elevated levels of both NKFBIA mRNA and IkappaBalpha protein in OSCC tumour tissues and OSCC cell lines. Meanwhile, IkappaBalpha silencing resulted in the suppression of cell proliferation, migration and invasion in OSCC. In addition, we demonstrated that IkappaBalpha can mediate the OSCC stemness and epithelial-mesenchymal transition (EMT) characteristics by directly interacting with cathepsin B (CTSB) and thus, facilitating the progression toward carcinogenesis. More importantly, we identified Psammaplin A (PsA), a natural metabolite derived from marine sponges that would disrupt the IkappaBalpha-CTSB interaction via competition, thereby reducing oral spheres formation, cell viability and OSCC tumour growth in vivo, clearly demonstrating its potential as an effective therapeutic agent that specifically targets this oncogenic complex. In summary, we have unveiled a novel mechanism underlying the oncogenic role of IkappaBalpha-CTSB complex in OSCC, which may offer the therapeutic potential of targeting this complex with PsA for the treatment of OSCC.