Cell Bi­ol­ogy

The tran­scrip­tion fac­tor NF-κB is a key player in in­flam­ma­tion, can­cer de­vel­op­ment, and pro­gres­sion. NF-κB stim­u­lates cell pro­lif­er­a­tion, pre­vents apop­to­sis, and could pro­mote tumor an­gio­gen­e­sis as well as metas­ta­sis. Ex­tend­ing the com­monly ac­cepted role of NF-κB in can­cer for­ma­tion and pro­gres­sion, we sum­ma­rize in a re­cently pub­lished re­view that dif­fer­ent NF-κB 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-κB, and sug­gest a much more elab­o­rated mode of NF-κB reg­u­la­tion, in­di­cat­ing a tumor type-​specific up­reg­u­la­tion of the NF-κB sub­units. While non-​canonical NF-κB RELB sig­nal­ing is de­scribed to be mostly present in hema­to­log­i­cal can­cers, solid can­cers re­veal con­sti­tu­tive canon­i­cal NF-κB RELA or c-REL ac­tiv­ity (see Fig. 6). Based on these find­ings, our cur­rent re­search aims to un­der­stand the dis­tinct roles of NF-κB 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-κB-​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). 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-κB-​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.