We now know that progastrins (PG) and insulin-like growth factors (IGFs) exert potent proliferative and anti- apoptotic effects on colon cancer (CRC) cells and can potentially function as co-carcinogens during all phases of colorectal carcinogenesis. Dietary agents, such as curcumin, inhibit the growth of CRC cells and inhibit colon carcinogenesis at both the pre-malignant and post-malignant stages of the disease. It is, however, not known if curcumin can inhibit the growth factor effects of autocrine and/or endocrine PG and IGF-II during colon carcinogenesis. Our preliminary studies suggest that the inhibitory effects of curcumin are attenuated in the presence of growth factors, such as IGF-II and PG; surprisingly the degree of attenuation was significantly higher in the presence of IGF-II than in the presence of PG. Therefore, the major hypothesis of our grant proposal is that the inhibitory efficacy of curcumin will be dictated by either the circulating growth factor profile of animal models or by the autocrine growth factors in CRC cells. To address this hypothesis, in Aim 1, we will develop isogenic cell lines that either express PG or IGF-II, and examine the pro-apoptotic and anti-proliferative potency of curcumin on these cells. Inhibitory effects of curcumin on intact colonic crypt cells, prepared from either transgenic mice over-expressing PG or IGFs or prepared from wild type mice, will also be examined.
In Aim 2, we will examine dose-dependent effects of dietary curcumin against all phases of colon carcinogenesis in transgenic mice over-expressing PG or IGF-II, either in the circulation or locally within the intestinal mucosa. The intracellular pathways that mediate anti-apoptotic vs proliferative effects of PG and IGFs, on CRC and intestinal epithelial (IEC) cells, are being currently examined in our laboratory. The mechanisms by which curcumin inhibits the growth factor effects of IGFs and PG are unknown at the present time.
In Aim 3 we will examine the effect of curcumin on the phosphorylation/dephosphorylation of several kinases/phosphatases that are activated in response to PG or IGF-II in isogenic CRC and IEC cells. The above experiments will allow us to learn for the first time the relative effectiveness of curcumin on colon carcinogenesis in the presence of growth factors relevant to the etiology of the disease. The results of these studies are expected to help in developing mechanism-based strategies for preventative/treatment protocols for CRCusing curcumin like agents.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA114264-03
Application #
7342501
Study Section
Special Emphasis Panel (ZRG1-CDP (01))
Program Officer
Perloff, Marjorie
Project Start
2006-02-06
Project End
2009-12-31
Budget Start
2008-01-01
Budget End
2008-12-31
Support Year
3
Fiscal Year
2008
Total Cost
$208,202
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Neurosciences
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Kantara, Carla; O'Connell, Malaney Ravae; Luthra, Gurinder et al. (2015) Methods for detecting circulating cancer stem cells (CCSCs) as a novel approach for diagnosis of colon cancer relapse/metastasis. Lab Invest 95:100-12
Kantara, Carla; O'Connell, Malaney; Sarkar, Shubhashish et al. (2014) Curcumin promotes autophagic survival of a subset of colon cancer stem cells, which are ablated by DCLK1-siRNA. Cancer Res 74:2487-98
Sarkar, Shubhashish; Kantara, Carla; Singh, Pomila (2012) Clathrin mediates endocytosis of progastrin and activates MAPKs: role of cell surface annexin A2. Am J Physiol Gastrointest Liver Physiol 302:G712-22
Sarkar, Shubhashish; Kantara, Carla; Ortiz, Ixiu et al. (2012) Progastrin overexpression imparts tumorigenic/metastatic potential to embryonic epithelial cells: phenotypic differences between transformed and nontransformed stem cells. Int J Cancer 131:E1088-99
Sarkar, Shubhashish; Swiercz, Rafal; Kantara, Carla et al. (2011) Annexin A2 mediates up-regulation of NF-?B, ?-catenin, and stem cell in response to progastrin in mice and HEK-293 cells. Gastroenterology 140:583-595.e4
Singh, Pomila; Sarkar, Shubhashish; Umar, Shahid et al. (2010) Insulin-like growth factors are more effective than progastrin in reversing proapoptotic effects of curcumin: critical role of p38MAPK. Am J Physiol Gastrointest Liver Physiol 298:G551-62
Chandrakesan, Parthasarathy; Ahmed, Ishfaq; Anwar, Tariq et al. (2010) Novel changes in NF-{kappa}B activity during progression and regression phases of hyperplasia: role of MEK, ERK, and p38. J Biol Chem 285:33485-98
Umar, Shahid; Sarkar, Shubhashish; Wang, Yu et al. (2009) Functional cross-talk between beta-catenin and NFkappaB signaling pathways in colonic crypts of mice in response to progastrin. J Biol Chem 284:22274-84
Umar, S; Sarkar, S; Cowey, S et al. (2008) Activation of NF-kappaB is required for mediating proliferative and antiapoptotic effects of progastrin on proximal colonic crypts of mice, in vivo. Oncogene 27:5599-611
Li, Qian; Deng, Xiaoling; Singh, Pomila (2007) Significant increase in the aggressive behavior of transgenic mice overexpressing peripheral progastrin peptides: associated changes in CCK2 and serotonin receptors in the CNS. Neuropsychopharmacology 32:1813-21

Showing the most recent 10 out of 11 publications