Michael Karin
University of California, San Diego
La Jolla, CA

Connecting Inflammation and Cancer Through the IKK-NF-kB Nexus

A link between inflammation and cancer has long been suspected but the exact molecular mechanisms connecting the two were not known. It is currently estimated that at least 20% of cancer mortality is associated with infection and inflammation. Thus understanding the underlying pathogenic mechanisms is of great importance. We have proposed that NF-kB transcription factors play a critical role in connecting inflammation to cancer and after elucidating the role of the IkB kinase (IKK) complex in NF-kB activation we have set out to examine this hypothesis. Using mice bearing mutations in the genes coding for the IKKb and IKKa catalytic subunits we found evidence for a critical tumor promoting role for IKKb and more recently identified a role for IKKa in the promotion of prostate cancer metastasis. Whereas the major tumor promoting function of IKKb is dependent on NF-kB activation, the pro-metastatic function of IKKa is NF-kB independent. In addition to illustrating the critical role of the IKK catalytic subunits in linking inflammation and cancer, these results also identify new targets for development novel types of anti-cancer therapies. Instead of targeting the cancer cell itself, such therapeutics should target processes that occur within inflammatory cells that are essential for cancer development and progression.