The broad goal of the project is to understand the mechanisms by which purified dietary compounds prevent the growth and development of tumors. Suring the past cycle, we have identified that curcumin inhibits epidermal growth factor mediated signaling through its cognate receptor EGFR thereby inhibiting AKT activation. We have recently identified a novel protooncogene which activates the Notch-mTOR-AKT signaling pathway. In addition, we have identified a novel compound marmelin from the Indian Medicinal plant Aegle marmelos. In preliminary studies, we have determined that marmelin inhibits colon cancer cell growth in culture and in tumor xenografts through the TNF-mediated pathway. We have also identified that both curcumin and marmelin modulate microRNA expression. Based on these observations, we propose three specific aims.
In Aim 1, we will determine the efficacy of a combination of curcumin and marmelin in preventing intestinal and colonic tumorigenesis in the AOM/DSS-induced mouse colon cancer model. Here, we will perform a series of single and combination treatment studies in mice that have initiated inflammation and determine whether the combination is more potent in inhibiting colitis induced cancers.
In Aim 2, we will determine the mechanism of curcumin- and marmelin-mediated suppression of RBM3. Here, we identify the regions in the RBM3 promoter that is regulated by the actions of the two compounds. In addition, we will determine the effect of the compounds on colon tumor growth and angiogenesis under condition of RBM3 overexpression.
In Aim 3, we propose to determine whether the Notch-mTOR-Akt pathway affects the activity of the two compounds by modulating their expression using specific inhibitors. In addition, we will determine the role of specific microRNAs that affect this pathway on the activity of the two compounds. Upon completion of the project, we will have favorable, compelling evidence for initiating clinical trials for the two compounds as chemopreventive agents.

Public Health Relevance

Cancer is the leading cause of death in the United States. Understanding how the normal cell progresses to a cancer will aid in our developing novel therapies for this dreaded disease. We have identified a protooncogene, RBM3 whose expression is increased in cancer cells. Overexpressing RBM3 protein causes a normal cell to become transformed into a cancer cell. We have also identified a novel compound from the Indian herb Aegle marmelos. We have determined in preliminary studies that this compound synergizes with curcumin to inhibit colon cancer growth. Our current proposal deals with determining the mechanism by which the two compounds, curcumin and marmelin inhibit colon cancer from developing. . We expect that the work will lead to a better understanding of the tumorigenesis process and identify novel methods to stop or slow down tumorigenesis.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Chemo/Dietary Prevention Study Section (CDP)
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Riscuta, Gabriela
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University of Kansas
Schools of Medicine
Kansas City
United States
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Kaushik, Gaurav; Venugopal, Anand; Ramamoorthy, Prabhu et al. (2015) Honokiol inhibits melanoma stem cells by targeting notch signaling. Mol Carcinog 54:1710-21
Ramalingam, Satish; Subramaniam, Dharmalingam; Anant, Shrikant (2015) Manipulating miRNA Expression: A Novel Approach for Colon Cancer Prevention and Chemotherapy. Curr Pharmacol Rep 1:141-153
Neradugomma, Naveen K; Subramaniam, Dharmalingam; Tawfik, Ossama W et al. (2014) Prolactin signaling enhances colon cancer stemness by modulating Notch signaling in a Jak2-STAT3/ERK manner. Carcinogenesis 35:795-806
Kaushik, Gaurav; Kwatra, Deep; Subramaniam, Dharmalingam et al. (2014) Honokiol affects melanoma cell growth by targeting the AMP-activated protein kinase signaling pathway. Am J Surg 208:995-1002; discussion 1001-2
Kwatra, Deep; Venugopal, Anand; Standing, David et al. (2013) Bitter melon extracts enhance the activity of chemotherapeutic agents through the modulation of multiple drug resistance. J Pharm Sci 102:4444-54
He, Zhiyun; Subramaniam, Dharmalingam; Zhang, Zhongtao et al. (2013) Honokiol as a Radiosensitizing Agent for Colorectal cancers. Curr Colorectal Cancer Rep 9:
Ahmed, Ishfaq; Roy, Badal; Chandrakesan, Parthasarathy et al. (2013) Evidence of functional cross talk between the Notch and NF-ýýB pathways in nonneoplastic hyperproliferating colonic epithelium. Am J Physiol Gastrointest Liver Physiol 304:G356-70
Subramaniam, Dharmalingam; Periyasamy, Giridharan; Ponnurangam, Sivapriya et al. (2012) CDK-4 inhibitor P276 sensitizes pancreatic cancer cells to gemcitabine-induced apoptosis. Mol Cancer Ther 11:1598-608
Sahoo, Kaustuv; Dozmorov, Mikhail G; Anant, Shrikant et al. (2012) The curcuminoid CLEFMA selectively induces cell death in H441 lung adenocarcinoma cells via oxidative stress. Invest New Drugs 30:558-67
Kaushik, Gaurav; Ramalingam, Satish; Subramaniam, Dharmalingam et al. (2012) Honokiol induces cytotoxic and cytostatic effects in malignant melanoma cancer cells. Am J Surg 204:868-73

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