Abstract
Aim: Extracellular superoxide dismutase (ECSOD) and the cysteine/glutamate transporter (Cys)/(xCT) are tumor microenvironment (TME) redox state homeostasis regulators. Altered expression of ECSOD and xCT can lead to imbalance of the TME redox state and likely have a profound effect on cancer invasion. In the present study, we investigated whether ECSOD and xCT could be therapeutic targets for prostate cancer (PCa) invasion. Results: Immunohistochemistry of tumor microarray PCa tissues (N = 165) with high Gleason scores indicated that xCT protein expression is significantly increased while ECSOD protein expression is significantly decreased. Metastatic PCa indicated ECSOD protein expression is significantly decreased in epithelial area whereas xCT protein expression is significantly increased in stromal area. Furthermore, inhibition of extracellular O 2 •- by overexpression of ECSOD or alteration of the extracellular Cys/CySS ratio by knockdown of xCT protein inhibited PCa cell invasion. Simultaneous overexpression of ECSOD and knockdown xCT inhibited PCa cell invasion more than overexpression of ECSOD or knockdown of xCT alone. In the co-culturing system, simultaneous overexpression of ECSOD and knockdown of xCT in prostate stromal WPMY-1 cells inhibited PCa cell invasiveness more than overexpression of ECSOD alone. The decrease in PCa invasion correlated with increased of extracellular H 2 O 2 levels. Notably, overexpression of catalase in TME reversed the inhibitory effect of ECSOD on cancer cell invasion. Conclusion: Impaired ECSOD activity and an upregulated of xCT protein expression may be clinical features of an aggressive PCa, particularly metastatic cancers and/or those with a high Gleason score. Therefore, shifting the extracellular redox state toward an oxidizing status by targeted modulation of ECSOD and xCT, in both cancer and stromal cells, may provide a greater strategy for potential therapeutic interventions of aggressive PCa.
| Original language | English |
|---|---|
| Pages (from-to) | 99-109 |
| Number of pages | 11 |
| Journal | Free Radical Biology and Medicine |
| Volume | 117 |
| DOIs | |
| State | Published - Mar 2018 |
Bibliographical note
Publisher Copyright:© 2018 Elsevier Inc.
Funding
This work was supported mainly by NIH grants CA188792 to Dr. Chaiswing. Our research utilized the service facilities of the Biospecimen Procurement and Translational Pathology Shared Resource Facility, the Flow Cytometer Shared Resource Facility, and the Biostatistics and Bioinformatics Shared Resource Facility, which were funded by a Markey Cancer Center support grant ( P30 CA177558 ). The authors thank 1) Dr. Dean Jones and Dr. Bill Yang of Emory University, GA, who provided technical support for measurements of thiols in the media, and 2) Drs. Chi Wang and Liu Jinpeng, the Markey Biostatistics and Bioinformatics Shared Resource facility, who provided assistance with Oncomine data analysis. We would like to dedicate this article to the memory of Dr. Terry D. Oberley. His dedication to the field of free radical biology and medicine was an inspiration to all of us. Appendix A
| Funders | Funder number |
|---|---|
| Markey Cancer Center | P30 CA177558 |
| National Institutes of Health (NIH) | |
| National Childhood Cancer Registry – National Cancer Institute | R21CA188792 |
Keywords
- ECSOD
- Invasion
- Redox state
- xCT
ASJC Scopus subject areas
- Biochemistry
- Physiology (medical)
