Silencing of Autocrine Motility Factor Induces Mesenchymal-to-Epithelial Transition and Suppression of Osteosarcoma Pulmonary Metastasis

Abstract

Phosphoglucose isomerase (PGI) is a multifunctional enzyme that functions in glucose metabolism as a glycolytic enzyme catalyzing an interconversion between glucose and fructose inside the cell, while it acts as cytokine outside the cell, with properties that include autocrine motility factor (AMF)-regulating tumor cell motility. Overexpression of AMF/PGI induces epithelial-to-mesenchymal transition with enhanced malignancy. Recent studies have revealed that silencing of AMF/PGI resulted in mesenchymal-to-epithelial transition (MET) of human lung fibrosarcoma cells and breast cancer cells with reduced malignancy. Here, we constructed a hammerhead ribozyme specific against GUC triplet at the position G390 in the human, mouse, and rat AMF/PGI mRNA sequence. Mesenchymal human osteosarcoma MG-63, HS-Os-1, and murine LM8 cells were stably transfected with the ribozyme specific for AMF/PGI. The stable transfectant cells showed effective downregulation of AMF/PGI expression and subsequent abrogation of AMF/PGI secretion, which resulted in morphologic change with reduced growth, motility, and invasion. Silencing of AMF/PGI induced MET, in which upregulation of E-cadherin and cytokeratins, as well as downregulation of vimentin, were noted. The MET guided by AMF/PGI gene silencing induced osteosarcoma MG-63 to terminally differentiate into mature osteoblasts. Furthermore, MET completely suppressed the tumor growth and pulmonary metastasis of LM8 cells in nude mice. Thus, acquisition of malignancy might be completed in part by upregulation of AMF/PGI, and waiver of malignancy might also be controlled by downregulation of AMF/PGI. Cancer Res; 70(22); 9483-93. ©2010 AACR.

An In Vitro Cynomolgus Vascular Surrogate System for Preclinical Drug Assessment and Human Translation

“…Indeed, decreased expression of hexokinase 2 and glucose-6-phosphate isomerase genes has been associated with reduced cell growth. [39][40][41] We observed that these genes are also downregulated by statin treatment, leading to reduced glucose metabolism and consequent reduced cell proliferation, consistent with anticancer effects reported with statin treatment.Finally, we detected that the acetaldehyde dehydrogenase genes, ALDH1A1 and ALDH1B1, were downregulated by statin treatment. These enzymes are important in the ethanol degradation process whereby alcohol dehydrogenase oxidizes ethanol in the liver into acetaldehyde, which is then oxidized by acetaldehyde dehydrogenases into nontoxic acetic acid.…”

Cancer cells in epithelial-to-mesenchymal transition and tumor-propagating–cancer stem cells: distinct, overlapping or same populations

“…Conversely to EMT, suppression of autocrine motility factor in various cancer cell lines induces MET (Niinaka et al, 2010). Expression of GATA3 in a breast cancer cell also reverses EMT, that is, induces MET (Yan et al, 2010).…”

Inhibition of IRE1 modifies hypoxic regulation of G6PD, GPI, TKT, TALDO1, PGLS and RPIA genes expression in U87 glioma cells

“…It was shown that AMF/PGI mediates epithelial and mesenchymal phenotype conversions in breast cancer and its overexpression induces epithelial tomesen chymal transition with enhanced malig nancy and that silencing of AMF/PGI resulted in mesenchymaltoepithelial transition of human lung fibrosarcoma cells and breast cancer cells with re duced malignancy [24,25]. It was also shown that overexpression of AMF/PGI significantly contributes to the aggressive phenotype of human cancer, but downregulation of its expression and subsequent abrogation of AMF/PGI secretion is resulted in mor phologic change with reduced growth, motility, and invasion [25,26]. PGI/AFM also regulates endoplas mic reticulum stress and cell death through control of endoplasmic reticulum calcium release as well as promotes cell survival by the pAKT survival path way [27].…”