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J. Biol. Chem., Vol. 282, Issue 50, 36362-36369, December 14, 2007

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Down-regulation of Phosphoglucose Isomerase/Autocrine Motility Factor Expression Sensitizes Human Fibrosarcoma Cells to Oxidative Stress Leading to Cellular Senescence^*

From the Tumor Progression and Metastasis Program, Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, Michigan 48201

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.

Received for publication, July 31, 2007 , and in revised form, September 24, 2007.

^* This work was supported by NCI, National Institutes of Health Grant R01 CA51714 (to A. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ To whom correspondence should be addressed: 110 East Warren Ave., Detroit, MI 48201. Tel.: 313-578-4330; Fax: 313-833-7518; E-mail: raza{at}karmanos.org.

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