Inhibiting oncogenic signaling by sorafenib activates PUMA via GSK3β and NF-κB to suppress tumor cell growth

摘要: Aberrant Ras/Raf/MEK/ERK signaling is one of the most prevalent oncogenic alterations and confers survival advantage to tumor cells. Inhibition this pathway can effectively suppress cell growth. For example, sorafenib, a multi-kinase inhibitor targeting c-Raf other kinases, has been used clinically for treating advanced liver kidney tumors, also shown efficacy against malignancies. However, how inhibition by sorafenib drugs suppresses growth remains unclear. In study, we found that kills cancer cells activating PUMA (p53-upregulated modulator apoptosis), p53 target BH3-only Bcl-2 family protein. Sorafenib treatment induces in variety irrespective their status. Surprisingly, induction mediated IκB-independent activation nuclear factor (NF)-κB, which directly binds promoter activate its transcription. NF-κB requires glycogen synthase kinase 3β activation, subsequent ERK inhibition. Deficiency abrogates sorafenib-induced apoptosis caspase renders resistance colony formation xenograft assays. Furthermore, chemosensitization effect dependent on PUMA, involves concurrent through different pathways. BH3 mimetics potentiate anti-cancer effects restore sensitivity resistant Together, these results demonstrate key role PUMA-dependent therapeutic signaling. They provide rationale manipulating apoptotic machinery improve overcome therapies