Research / Clinical
Summary
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Michael Karin, PhD
Professor, Pharmacology
Tumor Growth, Invasion & Metastasis Program
Contact by Email
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Diseases/Research Topics
B Lymphocyte Development, Basic Cell Biology, Cancer, Inflammation, Inflammatory Processes that Lead to Malignant Transformation In Vivo, Responses to Extracellular Stimuli and Stress, Signal Transduction, IKKbeta
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-kappaB transcription factors play a critical role in connecting inflammation to cancer and after elucidating the role of the IkappB kinase (IKK) complex in NF-kappaB activation, we have set out to examine this hypothesis. Using mice bearing mutations in the genes coding for the IKKB and IKKalpha catalytic subunits, we found evidence for a critical tumor promoting role for IKKB and more recently identified a role for IKKalpha 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 IKKalpha 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.1-6
Relevant Publications:
Karin M, Cao Y, Greten FR and Li ZW. NF-kB in cancer: from innocent bystander to major culprit. Nat Rev Cancer 2, 301-310 (2002).
Greten FR, et al. IKKb links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118, 285-296 (2004).
Luo JL, Maeda S, Hsu LC, Yagita H and Karin M. Inhibition of NF-kappaB in cancer cells converts inflammation- induced tumor growth mediated by TNFalpha to TRAIL-mediated tumor regression. Cancer Cell 6, 297-305 (2004).
Maeda S, Kamata H, Luo JL, Leffert H and Karin M. IKKb couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell 121, 977-990 (2005).
Chang L, et al. The E3 ubiquitin ligase itch couples JNK activation to TNFalpha-induced cell death by inducing c-FLIP(L) turnover. Cell 124, 601-13 (2006).
Sakurai T, Maeda S, Chang L and Karin M. Loss of hepatic NF-kB activity enhances chemical hepatocarcinogenesis through sustained c-Jun N-terminal kinase 1 activation. Proc Natl Acad Sci U S A 103, 10544-51 (2006).
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