CAAX proteins - Martin Bergö
Our group has been interested in a biochemical pathway that modifies so-called CAAX proteins. CAAX proteins are involved in the development of both wide-spread and rare human diseases including cancer, aging, and inflammatory diseases.
Over the past 10 years, we have defined the importance of the enzymes in this pathway, and their involvement in disease pathogenesis and usefulness as therapeutic targets. We have used a wide-range of research platforms from molecular and translational approaches to clinical epidemiology-based analyses. Funding from the US, EU, and Swedish agencies, strong support from the University of Gothenburg, and many awards and prizes have provided us with unique possibilities to perform curiosity-driven research and the resources to capitalize on unexpected findings.
Antioxidants increased invasive capacities of human and mouse melanoma cells by boosting the glutathione system and activating RHOA. The image shows invasion of melanoma cells expressing the stem cell marker nestin (brown staining at left) in a lymph node metastasis.
Unexpected findings and cumulative knowledge have raised exciting new questions
We recently found, serendipitously, that antioxidants, which are believed to protect against cancer, actually accelerates tumor progression and reduces survival in mice with lung cancer—a finding that explains a decades-old mystery of why antioxidants fail to protect against cancer in clinical trials (selected publications ref 2). The study sparked a heated debate and received world-wide attention from news media, likely because many people pin their hopes of staying cancer-free on antioxidant-rich foods or supplements and many companies exploit these hopes. Second, through our cumulative knowledge on CAAX protein processing (e.g., selected publications refs 3–5), we discovered that targeting ICMT blocks the proliferation of malignant melanoma cells, including those with acquired resistance to BRAF-inhibitors (a major clinical problem), and improves survival in mice with metastasizing melanoma (unpublished). Malignant melanoma increases steadily in incidence and numbers of deaths and our findings have also prompted us to make a large-scale attack on the melanoma problem.
Antioxidants markedly increased metastasis in this mouse model of malignant melanoma (BrafCA/+; Ptenfl/fl; Tyr-ER-Cre+/0).
We are now addressing a host of exciting questions: What is the impact of antioxidants in patients with increased risks of lung cancer and melanoma? Could antioxidants such as vitamin E and beta-carotene induce metastasis of benign lung and skin tumors? What are the molecular events that drive lung and melanoma initiation, progression, and metastasis? Can we culture lung and melanoma tumors in mice, use the mice as surrogate hosts to screen for effective drugs, and then use this information to guide clinical decisions in real-time? Could newly developed ICMT inhibitors prevent metastasis in mouse models of malignant melanoma and should the inhibitors be tested in human clinical trials? Our outstanding team of basic and clinical researchers are now addressing each of these questions.
Reduced ICMT expression improved health and survival of Zmpste24-deficient mice – a mouse model of progeria.
1. Antioxidants can increase melanoma metastasis in mice.
Sci Transl Med 2015 Oct;7(308):308re8
2. Oncogene-induced senescence underlies the mutual exclusive nature of oncogenic KRAS and BRAF.
Oncogene 2016 Mar;35(10):1328-33
3. Wild-type KRAS inhibits oncogenic KRAS-induced T-ALL in mice.
Leukemia 2015 May;29(5):1032-40
4. Antioxidants accelerate lung cancer progression in mice.
Sci Transl Med 2014 Jan;6(221):221ra15
5. Targeting isoprenylcysteine methylation ameliorates disease in a mouse model of progeria.
Science 2013 Jun;340(6138):1330-3
6. Targeting GGTase-I activates RHOA, increases macrophage reverse cholesterol transport, and reduces atherosclerosis in mice.
Circulation 2013 Feb;127(7):782-90
7. Geranylgeranyltransferase type I (GGTase-I) deficiency hyperactivates macrophages and induces erosive arthritis in mice.
J. Clin. Invest. 2011 Feb;121(2):628-39