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Abstract
The ubiquitin-proteasome pathway degrades ubiquitinated proteins to remove damaged or misfolded protein and thus plays an important role in the maintenance of many important cellular processes. Because the pathway is also crucial for tumor cell growth and survival, proteasome inhibition by specific inhibitors exhibits potent antitumor effects in many cancer cells. xCT, a subunit of the cystine antiporter system xc−, plays an important role in cellular cysteine and glutathione homeostasis. Several recent reports have revealed that xCT is involved in cancer cell survival; however, it was unknown whether xCT affects the cytotoxic effects of proteasome inhibitors. In this study, we found that two stress-inducible transcription factors, Nrf2 and ATF4, were upregulated by proteasome inhibition and cooperatively enhance human xCT gene expression upon proteasome inhibition. In addition, we demonstrated that the knockdown of xCT by small interfering RNA (siRNA) or pharmacological inhibition of xCT by sulfasalazine (SASP) or (S)-4-carboxyphenylglycine (CPG) significantly increased the sensitivity of T24 cells to proteasome inhibition. These results suggest that the simultaneous inhibition of both the proteasome and xCT could have therapeutic benefits in the treatment of bladder tumors.
ACKNOWLEDGMENTS
We thank Fumiko Tsukidate for technical assistance.
This study was financially supported by MEXT/JSPS KAKENHI grants 20117010 and 25293064, a Hirosaki University Institutional Research Grant, and a research grant from the Uehara Memorial Foundation to K.I. and a Priority Research Grant for Young Scientists Designated by the President of Hirosaki University and grants from the Karoji Memorial Fund for Medical Research of Hirosaki University, Hirosaki University School of Medicine, to J.M.
We have no conflict of interest.