Despite the best screening efforts to identify and remove colon polyps, colon cancer remains a leading cause of cancer related morbidity and mortality, both in the US and around the world. Also, current therapeutics while good in removing most cancer cells are not adequate because they leave some cells behind. This is because these cells can reemerge and develop a fresh tumor, which in many cases can manifest in a different organ due to metastasis. The advantage of using natural products that originate from fruits and vegetables over synthetic agents for preventing cancer is that they promote human health without recognizable side effects. In this regard, we have recently shown that bitter melon extracts (BME) inhibit the growth of DCLK1+ cells. We have now discovered that charantin, an active ingredient in the extracts is a potent inhibitor of colon cancer growth. The goal of the current project is to further characterize charantin and generate preclinical data as a dietary agent for the prevention of colon cancer. In preliminary studies, we have determined that charantin inhibits DCLK1 kinase activity and that of a related kinase CAMKIIa but not that of CAMKIIb and CAMKIV. Furthermore, charantin inhibits DCLK1 induced phosphorylation of AKT1/PKB. AKT1 is a serine-threonine protein kinase that is catalytically inactive until it is phosphorylated at two critical sites, Thr308 and Ser473. Various agents such as growth factors, and cytokines can rapidly activate the protein through the actions of phosphatidylinositol 3-kinase (PI3K). Upon activation, AKT1 induces phosphorylation of GSK-3b and also inhibits JNK activation. We have determined that charantin suppresses AKT1 activation and induces JNK. Moreover, JNK induces b-catenin phosphorylation, which in turn is subjected to b-TRCP independent, SIAH1- dependent ubiquitin-proteasome degradation pathway. We have also determined that charantin inhibits the growth of colon cancer cells in a novel culture method termed Tumor in a Dish (TiD). In this system, cells are grown in a three dimensional matrix that contains normal lung cells including normal epithelial cells, fibroblasts and endothelial cells. The model creates a near-in vivo tumor microenvironment including cell-cell contact, 3D- architecture, and the influence of different cell types. The observed selective killing of cancer cells in this system suggests that the compounds are highly specific and have good potency. Based on these preliminary results, we propose to further develop charantin as a dietary prevention agent and move it towards the clinic.
In aim 1, we propose to determine the role of PI3 kinase in charantin effect on DCLK1-mediated AKT1 activation.
In Aim 2, we propose to determine whether charantin affects AKT-mediated ?-catenin activation. Finally, in Aim 3, we will determine whether charantin induces JNK1 kinase and SIAH1 to induce ?-catenin degradation. We will determine the effect of the compound on DCLK1 expression, and on Akt phosphorylation, and b-catenin degradation. These studies will also aid in understanding a non-canonical pathway to suppress b-catenin signaling and identify novel biomarkers for the future clinical studies.
Colon cancer is a major cause of cancer morbidity and mortality in the United States, and current therapeutics are highly toxic. In this application, we propose to further develop Charantin, an active ingredient in bitter melon extracts as a dietary preventive agent against colon cancers. The proposed studies will lead to developing strategies and identifying biomarkers for future clinical studies.
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| Kumar, Dhruv; New, Jacob; Vishwakarma, Vikalp et al. (2018) Cancer-Associated Fibroblasts Drive Glycolysis in a Targetable Signaling Loop Implicated in Head and Neck Squamous Cell Carcinoma Progression. Cancer Res 78:3769-3782 |
| Spaw, Mark; Anant, Shrikant; Thomas, Sufi Mary (2017) Stromal contributions to the carcinogenic process. Mol Carcinog 56:1199-1213 |
| Angulo, Pablo; Kaushik, Gaurav; Subramaniam, Dharmalingam et al. (2017) Natural compounds targeting major cell signaling pathways: a novel paradigm for osteosarcoma therapy. J Hematol Oncol 10:10 |
| Blanco, Fernando F; Preet, Ranjan; Aguado, Andrea et al. (2016) Impact of HuR inhibition by the small molecule MS-444 on colorectal cancer cell tumorigenesis. Oncotarget 7:74043-74058 |
| Ponnurangam, Sivapriya; Dandawate, Prasad R; Dhar, Animesh et al. (2016) Quinomycin A targets Notch signaling pathway in pancreatic cancer stem cells. Oncotarget 7:3217-32 |
| Dandawate, Prasad R; Subramaniam, Dharmalingam; Jensen, Roy A et al. (2016) Targeting cancer stem cells and signaling pathways by phytochemicals: Novel approach for breast cancer therapy. Semin Cancer Biol 40-41:192-208 |
| Venugopal, Anand; Subramaniam, Dharmalingam; Balmaceda, Julia et al. (2016) RNA binding protein RBM3 increases ?-catenin signaling to increase stem cell characteristics in colorectal cancer cells. Mol Carcinog 55:1503-1516 |
| Dandawate, Prasad R; Subramaniam, Dharmalingam; Padhye, Subhash B et al. (2016) Bitter melon: a panacea for inflammation and cancer. Chin J Nat Med 14:81-100 |
| Ahmed, Ishfaq; Roy, Badal C; Subramaniam, Dharmalingam et al. (2016) An ornamental plant targets epigenetic signaling to block cancer stem cell-driven colon carcinogenesis. Carcinogenesis 37:385-96 |
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