Abstract 3858: Implications of the downregulation of stemness/reprogramming factor expression by ibuprofen and biguanides

Abstract

Abstract Cancer stem cells (CSCs) are thought to have the capacity to renew indefinitely, to initiate tumor formation, and to give rise to multiple non-tumorigenic progenies via asymmetric cell division. As a result of this phenotypic drift, an established tumor would consist of a mixture of CSC and non-CSC. Based on the current view, the CSC population is likely responsible for distant metastases, drug resistance and recurrence. However, the process by which this cell population is generated in a tumor mass has continued to be unclear. Based on our previous study (PNAS Vol. 110: 6097-6102, 2013), this process may involve nuclear reprogramming, namely the elevated expression of stemness/reprogramming factors (SOX2, OCT4, NANOG, LIN28, KLF4, MYC/MYCN, and those with equivalent functions). If so, it is conceivable that destabilization of these proteins would prevent or substantially slow down the generation of CSC compartment(s) within a tumor mass. Recently, we have reported that anti-inflammatory Ibuprofen and anti-diabetic biguanides destabilize MYC and MYCN in neuroblastoma cells. In this study, we have investigated the effects of Ibuprofen and Phenformin on stemness phenotypes of cancer cells (i.e., the expression of stemness factors) using the teratocarcinoma cell line NT2. NT2 cells were chosen as the experimental system because unlike many other cancer cell lines, they retain the expression of stemness/reprogramming factors. Furthermore, they express both MYC and MYCN proteins. Our data showed that high-dose/short-term treatment of NT2 cells with Phenformin and Ibuprofen significantly down-regulated the expression of MYC/MYCN, OCT4, SOX2, and NANOG. Moreover, the anti-stemness effect of Ibuprofen in the low-dose/long-term treatment was also evident (0.15 mM at Day 7 of the drug-treatment or 0.15 mM and 0.25 mM at Day 4). Experiments are underway to address the similar effect of low-dose/long-term treatment of Metformin and Phenformin in NT2 cells. We are also investigating a change in global gene expression in the drugs-treated NT2 cells, with the emphasis on stem cell-related genes and pathways. Results of these studies will help us better understand how these common drugs (anti-inflammation and diabetes medications) can be used in anti-cancer therapeutics, and more importantly, in cancer prevention, which is the key to eradication of this disease. Citation Format: Laura Grenlin, Tuan-Anh Tran, Sarah Lomahan, Naohiko Ikegaki, Xao X. Tang. Implications of the downregulation of stemness/reprogramming factor expression by ibuprofen and biguanides. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3858. doi:10.1158/1538-7445.AM2014-3858