2014-2015 Hormel Institute Annual Report
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PRSRT STD U.S. POSTAGE PAID Permit No. 32 Austin, MN 801 16th Avenue N.E. Austin, MN 55912-3679 Return Service Requested The research, partnerships and resources of The Hormel Institute are dedicated to a single purpose: Improving health through medical research. Today’s RESEARCH, Tomorrow’s CURES www.hi.umn.edu Cellular and Molecular Biology 6 Cancer Biomarkers and Drug Resistance 10 Molecular Chemoprevention and Therapeutics 12 Membrane Biochemistry 16 Structural Biology 20 The mission of The Hormel Institute is to conduct research and provide education Nutrition and Metabolism 22 Cell Death and Cancer Genetics 24 in the biological sciences with applications in medicine and agriculture. In pursuit Cancer Cell Biology and Translational Research 28 Today’s RESEARCH, of this mission, and as intended by its founders, The Hormel Institute generates Cellular Dynamics 30 fundamental knowledge and disseminates it to the scientific community worldwide. Tumor Microenvironment and Metastasis 34 Tomorrow’s CURES It also serves as a center of technical and educational expertise for the benefit of Immunoregulation of Autoimmune Diseases and Cancer 36 Translational Cancer Research 37 the Austin community, the surrounding region and the State of Minnesota. Cancer Epigenetics & Experimental Therapeutics 38 Stem Cells and Cancer 42 Cell Signaling and Tumorigenesis Section 44 Partners in Growth 49 Expansion 2014 - 16 54 2 The Hormel Institute “Today’s Research, Tomorrow’s Cures.” 3 Message from the Executive Director Dr. Zigang Dong During the 2014-15 year, we continued our focus on cancer research technology. Both additions are scheduled for completion by January 2016. because cancer already has surpassed heart disease as the No. 1 killer All of us from The Hormel Institute are very thankful for the generous of Americans under age 80. In fact, cancer is the leading cause of death support from the State of Minnesota, The Hormel Foundation, Hormel worldwide. Cancer affects all of us: women and men; poor and rich; old Foods Corporation, University of Minnesota, Mayo Clinic, 5th District and young; and all races. Eagles Cancer Telethon, Paint the Town Pink, and many other individuals and groups. In particular, I would like to thank Mr. Gary Ray, Mr. Jeff The Hormel Institute is a leading medical research institute making Ettinger, Mr. Richard Knowlton, Mr. Joel Johnson, Mrs. Bonnie Rietz, Mr. contributions to the identification and discovery of novel targets and Jerry Anfinson, and Mr. Steve Rizzi. We thank Drs. Eric Kaler and Brian agents for cancer prevention and therapy. We experienced continued Herman (University of Minnesota); and Drs. John Noseworthy, Glenn success during 2014-2015 in obtaining research funding and producing Forbes, Robert Diasio, and Greg Gores (Mayo Clinic) for their leadership major research breakthroughs, even in a national environment of overall and support. We thank our elected leaders, Minnesota Governor Mark decreased funding for research. Dayton; U.S. Senators Amy Klobuchar and Al Franken; U.S. Representative Tim Walz; Minnesota State Senator Dan Sparks; Minnesota State On May 28, 2014, we finished the design of a new building expansion and Representative Jeanne Poppe; Minnesota State Senator David Senjem; and held a groundbreaking ceremony with numerous local, state, and national Austin Mayor Tom Stiehm for their continued support. We remain deeply leaders. This 20-laboratory expansion is funded in part by $13.5 million grateful to our community, our partners, and our collaborators for giving in State of Minnesota bonding funds included in a bill supported by State us the gift of being able to work here. Their support and gifts allow today’s Senator Dan Sparks and State Representative Jeanne Poppe, and signed research to flourish and pave the way for tomorrow’s progress to continue. by Governor Mark Dayton. The Hormel Foundation matched the state’s $13.5 million commitment to construct the laboratory space on our east side and was a major contributor to the $4.5 million Live Learning Center “Most human cancers are preventable, or on our west side, featuring a multi-purpose room and 250-seat lecture treatable, if discovered at an early stage.” hall with theater-style seating and state-of-the-art global communications Dr. Zigang Dong Executive Director support 4 The Hormel Institute “Today’s Research, Tomorrow’s Cures.” 5 Cellular and Molecular Biology constitute a family of protein kinases that mediate signal transduction volume in a solar UV-induced skin carcinogenesis mouse model. A substantial Zigang Dong, M.D., Dr. P.H. downstream of the MAPK cascades. Phosphorylation of RSK and MSK1 reduction of phosphorylation in mitogen-activated protein kinase signaling Executive Director/Section Leader can be attenuated by aspirin intake. The widespread over-expression of was upregulated in human squamous cell carcinoma (SCC) and SUV-treated was observed in mice treated with caffeic acid either before or after solar UV McKnight Presidential Professor in Cancer Prevention EGFR occurs as a consequence of COX-2 activation in familial adenomatous mouse skin. Kaempferol – a natural flavonol found in tea, broccoli, grapes, exposure. Caffeic acid directly interacted with ERK1/2 and inhibited ERK1/2 Hormel/Knowlton Professor polyposis (FAP) patients. This study revealed a functional association between apples, and other plant sources – is known to have anticancer activity, but its activities in vitro. Importantly, we resolved the co-crystal structure of ERK2 COX-2 and EGFR expression during colon carcinogenesis and mechanisms and direct target(s) in cancer chemoprevention are unclear. Kinase provided new strategies for colon cancer prevention and therapy. array results revealed that kaempferol inhibited RSK2 and MSK1. Pull-down b. Discovery of novel mechanisms of RNF2 in cell death. assay results, ATP competition, and in vitro kinase assay data revealed that RNF2, also known as Ring1B/Ring2, is a component of the kaempferol interacts with RSK2 and MSK1 at the ATP-binding pocket and polycomb repression complex 1. RNF2 is highly expressed in inhibits their respective kinase activities. Mechanistic investigations showed many tumors, suggesting it might have an oncogenic function, that kaempferol suppresses RSK2 and MSK1 kinase activities to attenuate but the mechanism of action is unknown. We showed that SUV-induced phosphorylation of cAMP-responsive element binding protein knocking down RNF2 expression significantly inhibits both (CREB) and histone H3 in mouse skin cells. Kaempferol was a potent inhibitor cell proliferation and colony formation in soft agar and induces of SUV-induced mouse skin carcinogenesis. Further analysis showed that skin apoptosis in cancer cells. Knockdown of RNF2 in HCT116 from the kaempferol-treated mice exhibited a substantial reduction in SUV- p53+/+ cells resulted in significantly more apoptosis than was induced phosphorylation of CREB, c-Fos, and histone H3. Overall, our results observed in RNF2 knockdown HCT116 p53−/− cells, indicating identify kaempferol as a safe and novel chemopreventive agent against SUV- that RNF2 knockdown-induced apoptosis is at least partially, induced skin carcinogenesis that acts by targeting RSK2 and MSK1. dependent on p53. Various p53-targeted genes were increased in RNF2 knockdown cells. Further studies revealed that in RNF2 Chrysin (5,7-dihydroxyflavone), a natural flavonoid widely distributed in knockdown cells, the p53 protein level was increased, the half-life plants, reportedly has chemopreventive properties against various cancers. of p53 was prolonged, and p53 ubiquitination was decreased. The anti-cancer activity of chrysin observed in vivo studies, however, has (Left to right) Front row: Ann M. Bode, Ge Gao, Naomi Hamada, Qiushi Wang, Eunmiri Roh, Do Young Lim, Tatyana Zykova, Many proteins are Cancer is one of the leading causes of human In contrast, cells over-expressing RNF2 showed a decreased been disappointing. A chrysin derivative, referred to as compound 69407, Seung Ho Shin, Zigang Dong overexpressed only in cancer. death worldwide. By focusing on molecular p53 protein level, a shorter p53 half-life, and increased p53 ubiquitination. more strongly inhibited EGF-induced neoplastic transformation of JB6 P+ cells The epidermal growth factor mechanisms, we continue to discover the Importantly, we found that RNF2 directly binds with both p53 and MDM2 as compared with chrysin. It attenuated cell-cycle progression of EGF-stimulated Second row: Hanyong Chen, Ke Yao, Srinivasa Reddy Kanamata Reddy, Lichan Chen, Chengcheng Shi, Yi Zhang (green) is highly expressed key molecular events in cancer development well as promotes MDM2-mediated p53 ubiquitination. RNF2 over-expression cells at the G1 phase and inhibited the G1/S transition. Compound 69407 in skin tumors and is a major Third row: Yan Li, Wei He, JongBin Kim, Kun Yeong Lee, Sung-Young Lee, Margarita Malakhova, Wei Ya Ma as well as agents for cancer prevention and also could increase the half-life of MDM2 and inhibit its ubiquitination. The reduced tumor growth in the A431 mouse xenograft model and retinoblastoma Fourth row: KiBeom Bae, Joohyun Ryu, Hong-Gyum Kim, Hiroyuki Yamamoto, Tianshun Zhang, Tae-Gyu Lim. chemotherapy target in therapy. regulation of p53 and MDM2 stability by RNF2 also was observed during the phosphorylation at Ser795 and Ser807/811. Overall results indicated that breast cancer. compound 69407 is an ATP-noncompetitive cyclin-dependent kinase inhibitor Not pictured: Xiaoyu Chang,