It is well-established that tumor hypoxia (low O2) significantly contributes to chemo- and radio-therapy resistance. Under hypoxic conditions, ERK, HIF-1a (Hypoxic inducible factor), and p53 enhance tumor survival by increasing neo-vascularization, cell migration, metastasis, proliferation, and metabolism. Nitric oxide (NO) is an important signaling molecule, synthesized in and around many tumors. We have shown that like hypoxia, NO can post-translationally upregulate and increase the function of ERK, HIF-1a, and p53 in tumor cells. Small amounts of NO upregulate ERK, while incrementally larger amounts are necessary for the upregulation of HIF-1a and p53, respectively. Furthermore, we have shown that cellular metabolism of NO is inversely related to the O2 concentration. The goal of this proposal is to determine how hypoxia regulates NO-driven tumor cell migration via the post-translational regulation of ERK, HIF-1a, and p53. Based on our preliminary data, we hypothesize that the concentration of O2 in the tumor microenvironment is the ultimate upstream determinant of NO-driven tumor cell migration through ERK, HIF-1a, and p53 post-translational regulation. In support of this hypothesis we propose two specific aims: 1) Establish the O2-dependent mechanism of ERK, HIF-1a, and p53 regulation by NO. 2) Demonstrate that NO-driven tumor cell migration is a function of O2 concentration. These data will serve as a template model for predicting and understanding the behavior of tumors in vivo where NO is suspected to be a major driving force. These studies should lead to understanding, for the first time, the crucial yet unknown interrelationship between NO, O2, and protein regulation so that chemotherapeutic design may be specifically directed to target these important aspects of tumor physiology.
| Hickok, Jason R; Vasudevan, Divya; Jablonski, Kate et al. (2013) Oxygen dependence of nitric oxide-mediated signaling. Redox Biol 1:203-9 |
| Hickok, Jason R; Sahni, Sumit; Shen, Hong et al. (2011) Dinitrosyliron complexes are the most abundant nitric oxide-derived cellular adduct: biological parameters of assembly and disappearance. Free Radic Biol Med 51:1558-66 |
| Hickok, Jason R; Sahni, Sumit; Mikhed, Yuliya et al. (2011) Nitric oxide suppresses tumor cell migration through N-Myc downstream-regulated gene-1 (NDRG1) expression: role of chelatable iron. J Biol Chem 286:41413-24 |
| Hickok, Jason R; Thomas, Douglas D (2010) Nitric oxide and cancer therapy: the emperor has NO clothes. Curr Pharm Des 16:381-91 |
| Thomas, Douglas D; Ridnour, Lisa A; Isenberg, Jeffrey S et al. (2008) The chemical biology of nitric oxide: implications in cellular signaling. Free Radic Biol Med 45:18-31 |
