UNC Research Leader Sees Multiple Roles, Many Questions in NF-κB Activity

Albert S. Baldwin, Jr, PhD

Professor, Biology Associate Director, Basic Research, UNC Lineberger Comprehensive Cancer Center University of North Carolina

Chapel Hill, NC

Albert S. Baldwin, Jr, PhD, focuses on understanding the regulation and biological functions of NF-κB and its role in disease, particularly in cancer, in a laboratory he heads at the UNC Lineberger Comprehensive Cancer Center, a National Cancer Institute-designated center. The laboratory’s recent accomplishments include elucidating the mechanisms through which NF-κB interacts with oncoproteins.

1

What is the role of NF-κB in normal cells,

and how is it deregulated in cancer?

2

Please describe research in your lab as it relates to NF-κB signaling

in cancer.

3

How does NF-κB link cancer and inflammation, and how can this be exploited for therapy?

4

What is the most promising strategy for targeting NF-κB

in anticancer therapy?

5

What is the most significant question that remains to be answered

with respect to NF-κB in cancer?

NF-κB activation in normal cells is involved in response to stress (such as DNA damage), to promote cellular survival through the transcriptional regulation of key antiapoptotic genes. Additionally, NF-κB is activated in cells of the immune system (such as T cells) to promote proliferation and expansion of these cells. NF-κB is activated downstream of inflammatory cytokines to promote inflammatory responses such as the transcriptional upregulation of cytokines such as interleukin (IL)-6.Our group studies how NF-κB is activated by oncoproteins (eg, oncogenic/mutant Ras, Akt, PI3K) and by loss of tumor suppressors (eg, p53). We study what NF-κB does in cancer, including its role in promoting the function of tumor-initiating cells (so-called cancer stem cells). We also study the roles of different signaling arms of the NF-κB pathway (comparing canonical NF-κB signaling with noncanonical) in promoting cancer, and how multiple arms of the NF-κB pathway can be inhibited.The activation of NF-κB in cancer cells can be augmented by inflammatory signals from the microenvironment. An inflammatory environment surrounding the tumor promotes the proliferation and survival of malignant cells, promotes angiogenesis and metastasis, blocks adaptive immune responses, and blunts responses to chemotherapeutic agents. In this regard, NF-κB is known to be activated in the tumor microenvironment by factors secreted from the tumor. Thus, inhibition of NF-κB signaling as a cancer therapy is likely to have beneficial effects relative both to the tumor and to its microenvironment.Currently, the major effort is to develop specific inhibitors of the IKK complex upstream of NF-κB. Most of the effort has been directed at developing inhibitors of IKKβ, but IKKα can be important in the canonical NF-κB pathway and is clearly critical in the noncanonical pathway. Additionally, inhibitors that block the interaction between the catalytic components of IKK and its regulatory subunit, IKKγ, have been developed and show activity in some cancers.There are several important questions that remain unanswered, including:

• What is the involvement of the different arms of the NF-κB pathway (canonical, noncanonical) in promoting cancer, and what different roles does each pathway play?
• Is there a druggable target that could affect all NF-κB pathways?
• What antitumor functions of IKK/NF-κB signaling should be considered when these pathways are targeted in cancer? What compensatory pathways are upregulated when IKK is inhibited, and should they be inhibited simultaneously to provide an optimal therapeutic response?
• What functions does NF-κB play in cancer stem cells?
• What other oncoproteins function with NF-κB to promote cancer, and will inhibition of these pathways synergize with NF-κB inhibition as a cancer therapy approach?