Current therapies have little impact on the outcomes of pancreatic cancer. Interest is increasing in inhibitors of cancer stem cell (CSC) and cancer cell epithelial-mesenchymal transition (EMT) as potential innovative treatment for this disease. It is well accepted that EMT is an important initial step during the complicated process of cancer cell dissemination and metastasis. The presence of CSCs in pancreatic tumors is highly associated with cancer cell EMT that contributes to chemoresistant tumors prone to metastasis. Here we propose a novel strategy for inhibiting the RNA binding protein HuR as a regulator of cancer cell EMT and CSC. HuR is increasingly recognized as a pivotal factor in cancer-related gene expression. Through binding to 3'- untranslated regions regulation (3'-UTR) of mRNA and regulating mRNA turnover and translation, HuR contributes to many cellular processes, and enhances cancer cell invasion and metastasis. However, the mechanisms that HuR could be involved in cancer cell EMT have not been elucidated. In this project, we will study the mechanism by which HuR regulates cancer cell EMT, using a novel HuR inhibitor St-3. Compound St-3 was initially synthesized as a novel derivative of the HDAC inhibitor SAHA. Interestingly, St-3 has no HDAC inhibiting activity, but is a strong inhibitor of HuR. St-3 exhibited superior potency than SAHA in cytotoxicity, and inhibition of pancreatic cancer EMT and CSCs in vitro. Based on our exciting preliminary data, we hypothesize that that St-3 inhibits pancreatic cancer cell EMT and cancer stem cells (CSCs) through inhibition of HuR. We propose 2 specific aims to test our hypothesis.
Specific Aim 1. To determine HuR functional inhibition by St-3, with focus on genes related to EMT, CSC and metastasis. The working hypothesis is that St-3 disrupts HuR-RNA binding, leading to decay and reduced translation of mRNAs of the target genes critical for pancreatic cancer EMT, CSC and metastasis.
Specific Aim 2. To determine the effect of St-3 in vivo using a highly metastatic orthotopic pancreatic cancer mouse model. We will test the effect of St3 on tumor growth, metastasis, and on CSCs. Pancreatic cancer cells overexpressing HuR and cells containing a 3' UTR reporter of HuR target mRNA will also be utilized to determine St-3 effects and HuR/mRNA inhibition. If the proposed aims are accomplished, the possibility of HuR as a novel target for pancreatic cancer EMT and CSC inhibition would be emerging. The proposed studies would provide compelling mechanistic evidence for developing St-3 as a new class of HuR inhibitor with potential in inhibiting pancreatic cancer.
Current therapies have little impact on the outcomes of pancreatic cancer. We proposed here an innovative approach of inhibiting HuR-RNA interaction to target pancreatic cancer epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC), as EMT and CSC contribute substantially to chemo-resistant tumors prone to metastasis. As there is limited success to date on small molecule inhibitors for HuR-RNA interaction, our novel compound could provide a proof of principle for developing a new class of HuR inhibitor with potential in inhibiting pancreatic cancer.
|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|