NF-kappaB activation in cancer: a challenge for ubiquitination- and proteasome-based therapeutic approach.
Nuclear factor-kappa B (NF-kappaB) activation relies primarily on ubiquitin-mediated degradation of its inhibitor IkappaB. NF-kappaB plays an important role in many aspects of tumor development, progression, and therapy. Some types of cancer are characterized by constitutive NF-kappaB activity, whereas in others such activity is induced following chemotherapy. NF-kappaB-harboring tumors are generally resistant to chemotherapy and their eradication requires NF-kappaB inhibition. Here we describe the mechanisms of NF-kappaB activation in normal and tumor cells, review prevalent notions regarding the factor's contribution to tumorigenicity and discuss present and future options for NF-kappaB inhibition in cancer. The ubiquitination-mediated activation of NF-kappaB is intersected by another cancer-associated protein, beta-catenin. We, therefore, compare the related activation pathways and discuss the possibility of differential targeting of the involved ubiquitination machinery.
Amit
Sharon
S
The Lautenberg Center for Immunology, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
Ben-Neriah
Yinon
Y
D003546:Cysteine Endopeptidases / Q000378:metabolism / Q000627:therapeutic use*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D005260:Female; D006689:Hodgkin Disease / Q000378:metabolism; D006801:Humans; D008297:Male; D009097:Multienzyme Complexes / Q000378:metabolism / Q000627:therapeutic use*; D016328:NF-kappa B / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011987:Receptors, Steroid / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014452:Ubiquitins / Q000378:metabolism* / Q000627:therapeutic use; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D009097:Multienzyme Complexes; D016328:NF-kappa B; D011987:Receptors, Steroid; D015534:Trans-Activators; D014452:Ubiquitins; D051176:beta Catenin; D017346:Protein Serine-Threonine Kinases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex