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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA109269-10
Application #
8508864
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Riscuta, Gabriela
Project Start
2004-07-16
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
10
Fiscal Year
2013
Total Cost
$264,653
Indirect Cost
$88,218
Name
University of Kansas
Department
Physiology
Type
Schools of Medicine
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160
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
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
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
Gutheil, William G; Reed, Gregory; Ray, Amitabha et al. (2012) Crocetin: an agent derived from saffron for prevention and therapy for cancer. Curr Pharm Biotechnol 13:173-9
Subramaniam, Dharmalingam; Ramalingam, Satish; Linehan, David C et al. (2011) RNA binding protein CUGBP2/CELF2 mediates curcumin-induced mitotic catastrophe of pancreatic cancer cells. PLoS One 6:e16958
Subramaniam, Dharmalingam; Nicholes, Nathan D; Dhar, Animesh et al. (2011) 3,5-bis(2,4-difluorobenzylidene)-4-piperidone, a novel compound that affects pancreatic cancer growth and angiogenesis. Mol Cancer Ther 10:2146-56
He, Zhiyun; Subramaniam, Dharmalingam; Ramalingam, Satish et al. (2011) Honokiol radiosensitizes colorectal cancer cells: enhanced activity in cells with mismatch repair defects. Am J Physiol Gastrointest Liver Physiol 301:G929-37
Subramaniam, Dharmalingam; Ramalingam, Satish; Houchen, Courtney W et al. (2010) Cancer stem cells: a novel paradigm for cancer prevention and treatment. Mini Rev Med Chem 10:359-71
Bishnupuri, Kumar S; Luo, Qizhi; Sainathan, Satheesh K et al. (2010) Reg IV regulates normal intestinal and colorectal cancer cell susceptibility to radiation-induced apoptosis. Gastroenterology 138:616-26, 626.e1-2

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