Pancreatic cancer (PC) is an aggressive malignancy with one of the worst outcomes among all cancers. This could be partly due to the ability of PC cells to orchestrate in """"""""turning-on the switch"""""""" for migration, invasion, angiogenesis and metastatic processes during the early course of the disease. Therefore, there is a dire need for the development of novel strategies by which pancreatic tumor progression could be prevented. The constitutive activation of EGFR and Akt signaling, commonly seen in PC, is known to activate NF-:B, which transcriptionally regulates many genes contributing to aggressive tumor growth, angiogenesis and invasion, resulting in tumor progression. Moreover, recent studies have shown that the FoxM1 and Notch-1 signaling pathways are also activated in PC and appear to crosstalk with NF-:B (please see our preliminary results). However, how FoxM1 and Notch-1 crosstalk with NF-:B and regulate their downstream genes are not fully understood. Our preliminary data clearly suggest that the inactivation of FoxM1 and Notch-1 signaling causes down regulation of NF-:B, which contribute to the inhibition of cell growth, induction of apoptosis and inhibition of tumor cell invasion and angiogenesis. Based on our preliminary data and because of the lack of molecular understanding of the regulation and crosstalk between FoxM1, Notch-1 and NF-:B signaling, we hypothesize that further understanding of the molecular crosstalk between FoxM1, Notch- 1 and NF-:B, and their down-regulation by a novel agent could be an effective approach for designing better strategies for the prevention of pancreatic tumor progression. We will test our hypothesis by accomplishing the following specific aims. We will (i) determine how FoxM1 and Notch-1 crosstalk with NF-:B and regulates their downstream genes, and determine the consequence of down regulation of FoxM1/Notch- 1/NF-:B in PC cell growth, apoptosis, tumor cell invasion and angiogenesis. Next, (ii) we will test whether the down regulation of FoxM1/Notch-1 signaling by our novel approach (such as the use of genistein) could not only inhibit invasion and promote apoptotic cell death but also sensitize PC cells to an EGFR-tyrosine kinase inhibitor (erlotinib) and gemcitabine-induced killing. We will also test whether the chemo-sensitizing effect of genistein is mechanistically associated with the down regulation of FoxM1/Notch-1/NF-:B signaling. Finally, (iii) we will conduct in vivo experiments (using both orthotopic mouse model and transgenic mouse models of PC) to recapitulate our in vitro findings by testing (a) whether genistein-induced down regulation of FoxM1/Notch-1/NF-:B signaling could sensitize PC cells to erlotinib and gemcitabine induced killing, and (b) whether the inhibition of tumor progression could correlate with the down regulation of FoxM1/Notch-1/NF-:B signaling in animal tumor tissues. The results of our research will aid in designing a novel and targeted approach for the prevention of tumor progression, which would be highly relevant to public health in general and especially for saving lives of patients diagnosed with this deadly disease.
This project is focused on elucidating the mechanism by which a chemopreventive agent could prevent pancreatic tumor progression. Therefore, this grant is related to the prevention of gastrointestinal malignancy. We hypothesize that genistein down-regulates FoxM1 and Notch-1 signaling, which in turn down-regulate NF-:B and its downstream genes, resulting in the inhibition of tumor progression. We will test our hypothesis by three specific aims using molecular approaches in vitro and by using animal models in vivo (both orthotopic mouse model and transgenic mouse models of PC).
|Li, Yiwei; Go, Vay Liang W; Sarkar, Fazlul H (2015) The Role of Nutraceuticals in Pancreatic Cancer Prevention and Therapy: Targeting Cellular Signaling, MicroRNAs, and Epigenome. Pancreas 44:1-10|
|Suresh, Raagini; Sethi, Seema; Ali, Shadan et al. (2015) Differential Expression of MicroRNAs in Papillary Thyroid Carcinoma and Their Role in Racial Disparity. J Cancer Sci Ther 7:145-154|
|Ali, Shadan; Ahmad, Aamir; Aboukameel, Amro et al. (2014) Deregulation of miR-146a expression in a mouse model of pancreatic cancer affecting EGFR signaling. Cancer Lett 351:134-42|
|Bao, Bin; Azmi, Asfar S; Li, Yiwei et al. (2014) Targeting CSCs in tumor microenvironment: the potential role of ROS-associated miRNAs in tumor aggressiveness. Curr Stem Cell Res Ther 9:22-35|
|Sethi, S; Ali, S; Sethi, S et al. (2014) MicroRNAs in personalized cancer therapy. Clin Genet 86:68-73|
|Tan, Yi; Wu, Qiong; Xia, Jun et al. (2013) Systems biology approaches in identifying the targets of natural compounds for cancer therapy. Curr Drug Discov Technol 10:139-46|
|Sethi, Sajiv; Li, Yiwei; Sarkar, Fazlul H (2013) Regulating miRNA by natural agents as a new strategy for cancer treatment. Curr Drug Targets 14:1167-74|
|Bao, Bin; Ahmad, Aamir; Azmi, Asfar S et al. (2013) Overview of cancer stem cells (CSCs) and mechanisms of their regulation: implications for cancer therapy. Curr Protoc Pharmacol Chapter 14:Unit 14.25|
|Ali, Ashhar S; Ahmad, Aamir; Ali, Shadan et al. (2013) The role of cancer stem cells and miRNAs in defining the complexities of brain metastasis. J Cell Physiol 228:36-42|
|Li, Yiwei; Kong, Dejuan; Ahmad, Aamir et al. (2013) Pancreatic cancer stem cells: emerging target for designing novel therapy. Cancer Lett 338:94-100|
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