Down-regulation of phosphoglucose isomerase/autocrine motility factor expression sensitizes human fibrosarcoma cells to oxidative stress leading to cellular senescence.
Phosphoglucose isomerase/autocrine motility factor (PGI/AMF) is a housekeeping gene product present in all cells, is an essential enzyme of catabolic glycolysis and anabolic gluconeogenesis, and regulates tumor cell growth and metastasis. Because glycolytic enzyme up-regulation of expression contributes to glycolytic flux, leading to increased of cell growth and a resistance to cellular stress of normal fibroblasts whereas down-regulation of PGI/AMF leads to mesenchymal-to-epithelial transition in tumor cells, we examined the involvement of PGI/AMF in overcoming cellular senescence in cancer cells. PGI/AMF cellular expression in HT1080 human fibrosarcoma was down-regulated by small interfering RNA methodology, which resulted in an increased sensitivity to oxidative stress and oxidative stress-induced cellular senescence. Signaling analysis revealed that the senescence pathway involving p21 cyclin-dependent kinase inhibitor was up-regulated in PGI/AMF knockdown cells and that superoxide dismutase is the upstream regulator protein of p21-mediated cellular senescence. A specific inhibitor of PGI/AMF induced cellular senescence and p21 expression in tumor cells exposed to an oxidative stress environment. Taken together, the results presented here suggest that PGI/AMF is involved in oxidative stress-induced cellular senescence and should bring novel insights into the control of cellular growth leading to a new methodology for cancer treatment.
Funasaka
Tatsuyoshi
T
Tumor Progression and Metastasis Program, Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, Michigan 48201, USA.
Hu
Huankai
H
Hogan
Victor
V
Raz
Avraham
A
D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D005354:Fibrosarcoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000628:therapy; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D005943:Gluconeogenesis / Q000235:genetics; D005956:Glucose-6-Phosphate Isomerase / Q000096:biosynthesis* / Q000235:genetics; D006019:Glycolysis / Q000235:genetics; D006801:Humans; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D018384:Oxidative Stress / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D013482:Superoxide Dismutase / Q000378:metabolism
D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D013482:Superoxide Dismutase; D005956:Glucose-6-Phosphate Isomerase