[Frontiers in Bioscience 16, 1172-1185, January 1, 2011]

NF-kappaB in lung cancer, a carcinogenesis mediator and a prevention and therapy target

Wenshu Chen, Zi Li, Lang Bai, Yong Lin

Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute, 2425 Ridgecrest DR. SE, Albuquerque, NM 87108, USA


1. Abstract
2. Introduction
3. NF-kappaB activation pathways
3.1. Protein components in the NF-kappaB family
3.2. The pathways leading to NF-kappaB activation
4. NF-kappaB's cellular functions
4.1. NF-kappaB and transcription
4.2. NF-kappaB and cell proliferation
4.3. NF-kappaB and apoptosis
5. NF-kappaB in lung carcinogenesis
5.1. NF-kappaB activation in lung cancer
5.1.1. Oncogene-mediated NF-kappaB activation
5.1.2. Inflammation-associated NF-kappaB activation
5.1.3. Carcinogen-induced NF-kappaB activation
5.1.4. Other NF-kappaB activation mechanisms
5.2. A lung tumor-promoting role of NF-kappaB in animal models
5.3.NF-kappaB in lung tumor angiogenesis and metastasis
6. Targeting NF-kappaB signaling in lung cancer therapy
6.1. Agents that inhibit NF-kappaB activation in lung cancer cells
6.1.1. Proteosome inhibitors
6.1.2. Non-steroidal anti-inflammatory drugs (NSAID) and other approved drugs
6.1.3. Natural products and their synthetic derivatives
6.1.4. Other NF-kappaB inhibitors
6.1.5. Indirect inhibition of NF-kappaB activation
6.2. Hope and possible benefits of inhibiting NF-kappaB in lung cancer therapy
6.2.1. Sensitization of cancer cells to apoptosis inducing therapeutic agents
6.2.2. Inhibition of cancer invasion and metastasis
6.2.3. Amelioration of malignant pleural effusion
7. Inhibiting NF-kappaB for lung cancer chemoprevention
8. Concerns about inhibition NF-kappaB in lung cancer therapy and prevention
9. Summary and perspective
10. Acknowledgement
11. References


Lung cancer ranks as the first malignant tumor killer worldwide. Despite the knowledge that carcinogens from tobacco smoke and the environment constitute the main causes of lung cancer, the mechanisms for lung carcinogenesis are still elusive. Cancer development and progression depend on the balance between cell survival and death signals. Common cell survival signaling pathways are activated by carcinogens as well as by inflammatory cytokines, which contribute substantially to cancer development. As a major cell survival signal, nuclear factor-kappaB (NF-kappaB) is involved in multiple steps in carcinogenesis and in cancer cell's resistance to chemo- and radio-therapy. Recent studies with animal models and cell culture systems have established the links between NF-kappaB and lung carcinogenesis, highlighting the significance of targeting NF-kappa signaling pathway for lung cancer treatment and chemoprevention. In this review, we summarize progresses in understanding the NF-kappaB pathway in lung cancer development as well as in modulating NF-kappaB for lung cancer prevention and therapy.