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J. Biol. Chem., Vol. 280, Issue 41, 34985-34996, October 14, 2005

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Tumor-suppressive Maspin Regulates Cell Response to Oxidative Stress by Direct Interaction with Glutathione S-Transferase^*

Shuping Yin, Xiaohua Li, Yonghong Meng, Russell L. Finley, Jr., Wael Sakr, Heng Yang, Neelima Reddy, and Shijie Sheng¶1

From the Department of Pathology, Center of Molecular Medicine and Genetics, and ^¶Protease Program of the Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201

Maspin, a novel serine protease inhibitor, suppresses tumor progression in several cancer models, including an in vivo model for prostate cancer bone metastasis. However, the molecular mechanism of maspin remains illusive, primarily because its molecular targets are unknown. To this end, we used a full-length maspin cDNA bait to screen against both a primary prostate tumor cDNA prey library and a HeLa cDNA prey library by the yeast two-hybrid method. We found that heat shock protein 90, glutathione S-transferase (GST), and heat shock protein 70 interacted with maspin with the highest frequencies. We confirmed the maspin/GST interaction using purified proteins, human epithelial cell lines, and human prostate tissues. A maspin variant that has a point mutation of Arg³⁴⁰ to Ala (Mas^R340A) showed a significantly decreased affinity for GST. Although purified maspin had no effect on the activity of purified GST in vitro, intracellular interaction between endogenous maspin and GST correlated with an elevated total GST activity in both MDA-MB-435- and DU145-derived stably transfected cells. Consistently, tumor cells treated with purified wild type maspin, but not Mas^R340A, enhanced cellular GST activity. Maspin expression in cancer cell lines also correlated with decreased basal levels of reactive oxygen species (ROS). Furthermore, H²O² treatment not only induced GST expression but also increased intracellular maspin/GST interaction, which was inversely correlated with the level of ROS generation. Conversely, maspin knockdown by small interfering RNA increased the basal, as well as H²O²-induced, ROS generation. Furthermore, the maspin effect on ROS generation was completely abolished by a GST inhibitor, indicating an essential role of GST in maspin-mediated cellular response to oxidative stress. Consistently, oxidative stress-induced vascular endothelial growth factor A expression was significantly inhibited in maspin-expressing cells. Together, our data suggest a new mechanism by which maspin, through its direct interaction with GST, may inhibit oxidative stress-induced ROS generation and vascular endothelial growth factor A induction, thus preventing further adverse effects on tumor genetics and stromal reactivity.

Received for publication, March 31, 2005 , and in revised form, June 23, 2005.

^* This work was supported by National Institutes of Health Grant CA84176, the Ruth Sager Memorial Fund, the Fund for Cancer Research (to S. S.), and Department of Defense DAMD17-03-1-0038 (to S. Y.). 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.

¹ To whom correspondence should be addressed: Dept. of Pathology, Wayne State University School of Medicine, 540 East Canfield Ave., Detroit, MI 48201. Tel.: 313-993-8197; Fax: 313-993-4112; E-mail: ssheng{at}med.wayne.edu.

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