Nuclear factor-kappa B and cancer: its role in prevention and therapy.
Cancer is a hyperproliferative disorder in which invasion and angiogenesis lead to tumor metastasis. Several genes that mediate tumorigenesis and metastasis are regulated by a nuclear transcription factor, nuclear factor kappa B (NF-kappaB). A heterotrimeric complex consisting of p50, p65, and IkappaBalpha, NF-kappaB is present in its inactive state in the cytoplasm. When NF-kappaB is activated, IkappaBalpha is degraded and p50-p65 heterodimer is translocated to the nucleus, binds the DNA (at the promoter region), and activates gene. Research within the last few years has revealed that NF-kappaB is activated by carcinogens, tumor promoters, inflammatory cytokines, and by chemotherapeutic agents. The activation of NF-kappaB can suppress apoptosis, thus promoting chemoresistance and tumorigenesis. Interestingly, however, most chemopreventive agents appear to suppress the activation of the NF-kappaB through inhibition of NF-kappaB signaling pathway. These chemopreventive agents also sensitize the tumors to chemotherapeutic agents through abrogation of NF-kappaB activation. Overall, these observations suggest that NF-kappaB is an ideal target for chemoprevention and chemosensitization. This article reviews evidence supporting this hypothesis.
Bharti
Alok C
AC
Cytokine Research Section, Department of Bioimmunotherapy, M. D. Anderson Cancer Center, University of Texas, Box 143, 1515 Holcomb Boulevard, Houston, TX 77030, USA.
Aggarwal
Bharat B
BB
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002273:Carcinogens / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D018890:Chemoprevention; D006801:Humans; D016328:NF-kappa B / Q000187:drug effects / Q000502:physiology*; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology* / Q000517:prevention & control; D009389:Neovascularization, Pathologic / Q000503:physiopathology
D000970:Antineoplastic Agents; D002273:Carcinogens; D016328:NF-kappa B