Cargando…

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

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 deat...

Descripción completa

Detalles Bibliográficos
Autores principales: Oh, Sang-Seok, Lee, Ki Won, Madhi, Hamadi, Jeong, Jin-Woo, Park, Soojong, Kim, Minju, Lee, Yerin, Han, Hyun-Tak, Hwangbo, Cheol, Yoo, Jiyun, Kim, Kwang Dong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084876/
https://www.ncbi.nlm.nih.gov/pubmed/32131547
http://dx.doi.org/10.3390/ijms21051710
_version_ 1783508823832526848
author Oh, Sang-Seok
Lee, Ki Won
Madhi, Hamadi
Jeong, Jin-Woo
Park, Soojong
Kim, Minju
Lee, Yerin
Han, Hyun-Tak
Hwangbo, Cheol
Yoo, Jiyun
Kim, Kwang Dong
author_facet Oh, Sang-Seok
Lee, Ki Won
Madhi, Hamadi
Jeong, Jin-Woo
Park, Soojong
Kim, Minju
Lee, Yerin
Han, Hyun-Tak
Hwangbo, Cheol
Yoo, Jiyun
Kim, Kwang Dong
author_sort Oh, Sang-Seok
collection PubMed
description 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.
format Online
Article
Text
id pubmed-7084876
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-70848762020-03-23 Cordycepin Resensitizes T24R2 Cisplatin-Resistant Human Bladder Cancer Cells to Cisplatin by Inactivating Ets-1 Dependent MDR1 Transcription Oh, Sang-Seok Lee, Ki Won Madhi, Hamadi Jeong, Jin-Woo Park, Soojong Kim, Minju Lee, Yerin Han, Hyun-Tak Hwangbo, Cheol Yoo, Jiyun Kim, Kwang Dong Int J Mol Sci Article 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. MDPI 2020-03-02 /pmc/articles/PMC7084876/ /pubmed/32131547 http://dx.doi.org/10.3390/ijms21051710 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Oh, Sang-Seok
Lee, Ki Won
Madhi, Hamadi
Jeong, Jin-Woo
Park, Soojong
Kim, Minju
Lee, Yerin
Han, Hyun-Tak
Hwangbo, Cheol
Yoo, Jiyun
Kim, Kwang Dong
Cordycepin Resensitizes T24R2 Cisplatin-Resistant Human Bladder Cancer Cells to Cisplatin by Inactivating Ets-1 Dependent MDR1 Transcription
title Cordycepin Resensitizes T24R2 Cisplatin-Resistant Human Bladder Cancer Cells to Cisplatin by Inactivating Ets-1 Dependent MDR1 Transcription
title_full Cordycepin Resensitizes T24R2 Cisplatin-Resistant Human Bladder Cancer Cells to Cisplatin by Inactivating Ets-1 Dependent MDR1 Transcription
title_fullStr Cordycepin Resensitizes T24R2 Cisplatin-Resistant Human Bladder Cancer Cells to Cisplatin by Inactivating Ets-1 Dependent MDR1 Transcription
title_full_unstemmed Cordycepin Resensitizes T24R2 Cisplatin-Resistant Human Bladder Cancer Cells to Cisplatin by Inactivating Ets-1 Dependent MDR1 Transcription
title_short Cordycepin Resensitizes T24R2 Cisplatin-Resistant Human Bladder Cancer Cells to Cisplatin by Inactivating Ets-1 Dependent MDR1 Transcription
title_sort cordycepin resensitizes t24r2 cisplatin-resistant human bladder cancer cells to cisplatin by inactivating ets-1 dependent mdr1 transcription
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084876/
https://www.ncbi.nlm.nih.gov/pubmed/32131547
http://dx.doi.org/10.3390/ijms21051710
work_keys_str_mv AT ohsangseok cordycepinresensitizest24r2cisplatinresistanthumanbladdercancercellstocisplatinbyinactivatingets1dependentmdr1transcription
AT leekiwon cordycepinresensitizest24r2cisplatinresistanthumanbladdercancercellstocisplatinbyinactivatingets1dependentmdr1transcription
AT madhihamadi cordycepinresensitizest24r2cisplatinresistanthumanbladdercancercellstocisplatinbyinactivatingets1dependentmdr1transcription
AT jeongjinwoo cordycepinresensitizest24r2cisplatinresistanthumanbladdercancercellstocisplatinbyinactivatingets1dependentmdr1transcription
AT parksoojong cordycepinresensitizest24r2cisplatinresistanthumanbladdercancercellstocisplatinbyinactivatingets1dependentmdr1transcription
AT kimminju cordycepinresensitizest24r2cisplatinresistanthumanbladdercancercellstocisplatinbyinactivatingets1dependentmdr1transcription
AT leeyerin cordycepinresensitizest24r2cisplatinresistanthumanbladdercancercellstocisplatinbyinactivatingets1dependentmdr1transcription
AT hanhyuntak cordycepinresensitizest24r2cisplatinresistanthumanbladdercancercellstocisplatinbyinactivatingets1dependentmdr1transcription
AT hwangbocheol cordycepinresensitizest24r2cisplatinresistanthumanbladdercancercellstocisplatinbyinactivatingets1dependentmdr1transcription
AT yoojiyun cordycepinresensitizest24r2cisplatinresistanthumanbladdercancercellstocisplatinbyinactivatingets1dependentmdr1transcription
AT kimkwangdong cordycepinresensitizest24r2cisplatinresistanthumanbladdercancercellstocisplatinbyinactivatingets1dependentmdr1transcription