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Article

Cordycepin Resensitizes T24R2 Cisplatin-Resistant Human Bladder Cancer Cells to Cisplatin by Inactivating Ets-1 Dependent MDR1 Transcription

1
Gene & Cell Therapy Team, Division of Drug Development & Optimization, New Drug Development Center, Osong Medical Innovation Foundation, Osongsaengmyung-ro 123, Osong-eup, Heungdeok-gu, Cheongju-si, Chungbuk 28160, Korea
2
Division of Applied Life Science (BK21 Plus), Gyeongsang National University, Jinju 52828, Korea
3
Freshwater Bioresources Utilization Bureau, Nakdonggang National Institute of Biological Resources, Sangju 37242, Korea
4
PMBBRC, Gyeongsang National University, Jinju 52828, Korea
5
Division of Life Science, Gyeongsang National University, Jinju 52828, Korea
*
Author to whom correspondence should be addressed.
Sang-Seok Oh and Ki Won Lee are co-first authors.
Int. J. Mol. Sci. 2020, 21(5), 1710; https://doi.org/10.3390/ijms21051710
Received: 21 January 2020 / Revised: 21 February 2020 / Accepted: 26 February 2020 / Published: 2 March 2020
Tumor cell resistance to anti-cancer drugs is a major obstacle in tumor therapy. In this study, we investigated the mechanism of cordycepin-mediated resensitization to cisplatin in T24R2 cells, a T24-derived cell line. Treatment with cordycepin or cisplatin (2 μg/mL) alone failed to induce cell death in T24R2 cells, but combination treatment with these drugs significantly induced apoptosis through mitochondrial pathways, including depolarization of mitochondrial membranes, decrease in anti-apoptotic proteins Bcl-2, Bcl-xL, and Mcl-1, and increase in pro-apoptotic proteins Bak and Bax. High expression levels of MDR1 were the cause of cisplatin resistance in T24R2 cells, and cordycepin significantly reduced MDR1 expression through inhibition of MDR1 promoter activity. MDR1 promoter activity was dependent on transcription factor Ets-1 in T24R2 cells. Although correlation exists between MDR1 and Ets-1 expression in bladder cancer patients, active Ets-1, Thr38 phosphorylated form (pThr38), was critical to induce MDR1 expression. Cordycepin decreased pThr-38 Ets-1 levels and reduced MDR1 transcription, probably through its effects on PI3K signaling, inducing the resensitization of T24R2 cells to cisplatin. The results suggest that cordycepin effectively resensitizes cisplatin-resistant bladder cancer cells to cisplatin, thus serving as a potential strategy for treatment of cancer in patients with resistance to anti-cancer drugs. View Full-Text
Keywords: cordycepin; cisplatin-resistance; resensitization; MDR1; Ets-1; PI3K cordycepin; cisplatin-resistance; resensitization; MDR1; Ets-1; PI3K
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MDPI and ACS Style

Oh, S.-S.; Lee, K.W.; Madhi, H.; Jeong, J.-W.; Park, S.; Kim, M.; Lee, Y.; Han, H.-T.; Hwangbo, C.; Yoo, J.; Kim, K.D. Cordycepin Resensitizes T24R2 Cisplatin-Resistant Human Bladder Cancer Cells to Cisplatin by Inactivating Ets-1 Dependent MDR1 Transcription. Int. J. Mol. Sci. 2020, 21, 1710. https://doi.org/10.3390/ijms21051710

AMA Style

Oh S-S, Lee KW, Madhi H, Jeong J-W, Park S, Kim M, Lee Y, Han H-T, Hwangbo C, Yoo J, Kim KD. Cordycepin Resensitizes T24R2 Cisplatin-Resistant Human Bladder Cancer Cells to Cisplatin by Inactivating Ets-1 Dependent MDR1 Transcription. International Journal of Molecular Sciences. 2020; 21(5):1710. https://doi.org/10.3390/ijms21051710

Chicago/Turabian Style

Oh, Sang-Seok; Lee, Ki W.; Madhi, Hamadi; Jeong, Jin-Woo; Park, Soojong; Kim, Minju; Lee, Yerin; Han, Hyun-Tak; Hwangbo, Cheol; Yoo, Jiyun; Kim, Kwang D. 2020. "Cordycepin Resensitizes T24R2 Cisplatin-Resistant Human Bladder Cancer Cells to Cisplatin by Inactivating Ets-1 Dependent MDR1 Transcription" Int. J. Mol. Sci. 21, no. 5: 1710. https://doi.org/10.3390/ijms21051710

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