Subunit-Specific Role of NF-kB in Cancer

 

 The transcription factor NF-kB is a key player in inflammation, cancer development, and progression. NF-kB stimulates cell proliferation, prevents apoptosis, and could promote tumor angiogenesis as well as metastasis. Extending the commonly accepted role of NF-kB in cancer formation and progression, we summarize in a recently published review that different NF-kB subunits have been shown to be active and of particular importance in distinct types of cancer (Kaltschmidt et al., 2018). Here,  overexpression data gained by database mining argue against a universal mechanism of cancer-mediated activation of NF-kB, and suggest a much more elaborated mode of NF-kB regulation, indicating a tumor type-specific upregulation of the NF-kB subunits. While non-canonical NF-kB RELB signaling is described to be mostly present in hematological cancers, solid cancers reveal constitutive canonical NF-kB RELA or c-REL activity (see above). Based on these findings, our current research aims to understand the distinct roles of NF-kB subunits and their upstream kinases in cancer cells in more detail. On methodical level, we apply CRISPR/Cas-mediated knockout strategies for guided deletions of NF-kB-subunits in human cells. In this regard, we recently observed TNF-mediated cell death only in human cells lacking IKK1 and IKK2 and not in single CRISPR/Cas-mediated IKK knockouts, suggesting that both IKK1 and IKK2 are required for functional TNF-signaling (Slotta et al., 2018)(see above). We further demonstrated a knockout of c-REL in human in human cervical cancer cells to result in significantly reduced proliferative behavior and a significant delay in the prometaphase of mitosis. Compared to the wild type, an increased resistance against chemotherapeutic agents was observable in c-REL knockout cells (Slotta et al., 2017), emphasizing direct clinical implications of NF-kB-signaling for the development of new treatment strategies.

 

KALTSCHMIDT, B., GREINERJ.F.W., KADHIM, H.M. & KALTSCHMIDT, C. 2018. Subunit-Specific Role of NF-kB in Cancer. Biomedicines.

SLOTTA, C., SCHLUTER, T., RUIZ-PERERA, L. M., KADHIM, H. M., TERTEL, T., HENKEL, E., HUBNER, W., GREINER, J. F. W., HUSER, T., KALTSCHMIDT, B. & KALTSCHMIDT, C. 2017. CRISPR/Cas9-mediated knockout of c-REL in HeLa cells results in profound defects of the cell cycle. PLoS One, 12, e0182373.

SLOTTA, C., STORM, J., PFISTERER, N., HENKEL, E., KLEINWACHTER, S., PIEPER, M., RUIZ-PERERA, L. M., GREINER, J. F. W., KALTSCHMIDT, B. & KALTSCHMIDT, C. 2018. IKK1/2 protect human cells from TNF-mediated RIPK1-dependent apoptosis in an NF-kappaB-independent manner. Biochim Biophys Acta.