RelB Expression Determines the Differential Effects of Ascorbic Acid in Normal and Cancer Cells

Authors

Xiaowei Wei, University of Kentucky
Yong Xu, University of KentuckyFollow
Fang Fang Xu, University of KentuckyFollow
Luksana Chaiswing, University of KentuckyFollow
David M. Schnell, University of KentuckyFollow
Teresa Noel, University of KentuckyFollow
Chi Wang, University of KentuckyFollow
Jinfei Chen, Nanjing Medical University, China
Daret K. St. Clair, University of KentuckyFollow
William H. St. Clair, University of KentuckyFollow

Abstract

Cancer cells typically experience higher oxidative stress than normal cells, such that elevating pro-oxidant levels can trigger cancer cell death. Although pre-exposure to mild oxidative agents will sensitize cancer cells to radiation, this pre-exposure may also activate the adaptive stress defense system in normal cells. Ascorbic acid is a prototype redox modulator that when infused intravenously appears to kill cancers without injury to normal tissues; however, the mechanisms involved remain elusive. In this study, we show how ascorbic acid kills cancer cells and sensitizes prostate cancer to radiation therapy while also conferring protection upon normal prostate epithelial cells against radiation-induced injury. We found that the NF-κB transcription factor RelB is a pivotal determinant in the differential radiosensitization effects of ascorbic acid in prostate cancer cells and normal prostate epithelial cells. Mechanistically, high reactive oxygen species concentrations suppress RelB in cancer cells. RelB suppression decreases expression of the sirtuin SIRT3 and the powerful antioxidant MnSOD, which in turn increases oxidative and metabolic stresses in prostate cancer cells. In contrast, ascorbic acid enhances RelB expression in normal cells, improving antioxidant and metabolic defenses against radiation injury. In addition to showing how RelB mediates the differential effects of ascorbic acid on cancer and normal tissue radiosensitivities, our work also provides a proof of concept for the existence of redox modulators that can improve the efficacy of radiotherapy while protecting against normal tissue injury in cancer settings.

Document Type

Article

Publication Date

3-2017

Notes/Citation Information

Published in Cancer Research, v. 77, issue 6, p. 1345-1356.

© 2017 American Association for Cancer Research

The copyright holder has granted the permission for posting the article here.

The document available for download is the authors' post-peer-review final draft of the article.

Digital Object Identifier (DOI)

https://doi.org/10.1158/0008-5472.CAN-16-0785

Funding Information

This work was supported mainly by NIH grants CA 049797 and CA 143428 to D.K. St. Clair and W.H. St. Clair. Additional support was provided by grants from the National Natural Science Foundation of China (Grant No. 81272469) and the Natural Science Foundation of Jiangsu Province (Grant No. BL2012016) to J. Chen. The research used service facilities funded by a Cancer Center support grant (P30 CA177558).

Related Content

Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

Repository Citation

Wei, Xiaowei; Xu, Yong; Xu, Fang Fang; Chaiswing, Luksana; Schnell, David M.; Noel, Teresa; Wang, Chi; Chen, Jinfei; St. Clair, Daret K.; and St. Clair, William H., "RelB Expression Determines the Differential Effects of Ascorbic Acid in Normal and Cancer Cells" (2017). Toxicology and Cancer Biology Faculty Publications. 81.
https://uknowledge.uky.edu/toxicology_facpub/81