264 - Myoglobin Regulates the Function of the E3 Ligase Parkin to Modulate Mitochondrial Fusion and Decrease Breast Cancer Tumor Progression

Abstract

In skeletal and cardiac muscles the monomeric heme protein myoglobin is known to modulate cellular oxygen and nitric oxide gradients to regulate hypoxic mitochondrial respiration. Recently, myoglobin has also been shown to be aberrantly expressed in breast cancer tumors and this expression is associated with better patient prognosis. Even though the underlying protective mechanism of myoglobin in breast cancer cells has not yet been elucidated, regulation of mitochondrial function has been implicated. Mitochondrial dynamics play a role in modulating cell cycle progression with prolonged mitochondrial fusion causing cell cycle arrest. Given that dysregulated and rapid cell proliferation is central to cancer pathogenesis, we hypothesized that myoglobin expression induces mitochondrial fusion to inhibit breast cancer cell proliferation and attenuate tumor growth. In this study, we use MDA-MB231 breast cancer cells to show that stable expression of human myoglobin significantly decreases cellular proliferation. This decreased proliferation is associated with markers of cell cycle arrest and caused by increased expression of mitofusin-1, a major inducer of mitochondrial fusion. In vivo experiments in a murine xenograft model utilizing MDA-MB231 cells expressing myoglobin demonstrate that tumor volume and weight trend lower in myoglobin expressing tumors compared to non-expressing tumors, and this is concomitant with an increase in mitochondrial fusion and cell cycle arrest markers. Ongoing studies are determining the mechanism by which myoglobin regulates the expression of mitofusin-1. The role of myoglobin as a catalyst of reactive oxygen species generation is being explored. Preliminary experiments suggest myoglobin dependent oxidation and decreased expression of the ubiquitin ligase parkin functions to mark mitofusin-1 for proteosomal degradation. These data suggest a novel role for myoglobin as a modulator of mitochondrial dynamics, cell proliferation, and tumor growth.