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NF-κB Signaling Pathways in Carcinogenesis

  • Harikrishna Nakshatri
Chapter

Abstract

Nuclear factor-kappaB (NF-κB) is a signal-activated transcription factor complex with two functional subunits and controls the expression of >600 genes in the human genome. This protein complex was initially identified and described as a nuclear protein complex uniquely present in cells that transcribe immunoglobulin light chain genes. Hence, its pro-oncogenic functions were studied only in the context of hematologic malignancies. However, subsequent studies showed the presence of this complex in almost all cell types. Early studies of this complex suggested only pro-oncogenic role, which triggered massive interest in both academia and industry in developing drugs targeting this transcription factor complex. Because NF-κB activation requires multiple enzymatic steps, it is one of the few transcriptional regulators that are therapeutically targetable. Recent studies, however, have revealed both tumor suppressor and pro-oncogenic functions depending on the cellular context, stage of the disease, and concomitant genomic aberration in cancer cells. During initiation stage of tumorigenesis, NF-κB activates senescence program and prevents damaged cells from proliferating. During later stage, it promotes tumorigenesis by activating anti-apoptotic, pro-inflammatory, pro-metastatic, and tumor-immune suppressive machineries. Amplifications, mutations, and rare deletions in various components of NF-κB pathway are observed in multiple cancer types, and IKKε among them is a proven oncogene and is amplified in >30% of breast cancers. These complexities in NF-κB activities need to be taken into consideration while designing clinical trials with drugs with NF-κB inhibitory activity. Although specific inhibitors of NF-κB are yet to enter oncology clinic, NF-κB is one of the targets of several FDA-approved drugs including bortezomib used for treating multiple myeloma.

Keywords

NF-κB IKK IκB Cytokines Growth factors Inflammation Immune therapy Chemoresistance 

Abbreviations

COX2

Cyclooxygenase 2

CSN5

COP9 signalosome 5

CXCL

Chemokine (C-X-C) ligand

CXCR

Chemokine (C-X-C) receptor

EGFR

Epidermal growth factor receptor

ERBB2

ERB-B2 receptor tyrosine kinase 2

FAS

Fas cell death receptor

FASL

FAS ligand

IAP

Inhibitor of apoptosis

IKK

IκB kinase

IL

Interleukin

IκB

Inhibitor of kappaB

MLL

Mixed lineage leukemia

MMP

Matrix metalloproteinase

MyoD

Myogenic differentiation 1

NF-κB

Nuclear factor-kappaB

PD-L1

Programmed death ligand 1

PIK3CA

Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha

SASP

Senescence-associated secretory phenotype

TNF

Tumor necrosis factor

ZEB

Zinc finger E-box-binding homeobox

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Departments of Surgery, Biochemistry and Molecular BiologyIndiana UniversityIndianapolisUSA

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