Overcoming TRAIL-resistance by sensitizing prostate cancer 3D spheroids with taxanes

Author:

Grayson Korie A.,Jyotsana NidhiORCID,Ortiz-Otero Nerymar,King Michael R.ORCID

Abstract

Three-dimensional spheroid cultures have been shown to better physiologically mimic the cell-cell and cell-matrix interactions that occur in solid tumors more than traditional 2D cell cultures. One challenge in spheroid production is forming and maintaining spheroids of uniform size. Here, we developed uniform, high-throughput, multicellular spheroids that self-assemble using microwell plates. DU145 and PC3 cells were cultured as 2D monolayers and 3D spheroids to compare sensitization of TRAIL-resistance cancer cells to TRAIL mediated apoptosis via chemotherapy based on dimensionality. Monocultured monolayers and spheroids were treated with soluble TRAIL alone (24 hr), DTX or CBZ alone (24 hr), or a combination of taxane and TRAIL (24 + 24 hr) to determine the effectiveness of taxanes as TRAIL sensitizers. Upon treatment with soluble TRAIL or taxanes solely, monolayer cells and spheroids exhibited no significant reduction in cell viability compared to the control, indicating that both cell lines are resistant to TRAIL and taxane alone in 2D and 3D. Pretreatment with CBZ or DTX followed by TRAIL synergistically amplified apoptosis in 2D and 3D DU145 cell cultures. PC3 spheroids were more resistant to the combination therapy, displaying a more additive effect in the DTX + TRAIL group compared to 2D. There was a downregulation of DR4/5 expression in spheroid form compared to monolayers in each cell line. Additionally, normal fibroblasts (NFs) and cancer-associated fibroblasts (CAFs) were cocultured with both PCa cell lines as spheroids to determine if CAFs confer additional resistance to chemotherapy. We determined that co-cultured spheroids show similar drug resistance to monocultured spheroids when treated with taxane plus TRAIL treatment. Collectively, these findings suggest how the third dimension and cocultures of different cell types effect the sensitization of androgen-independent prostate cancer cells to TRAIL, suggesting therapeutic targets that could overcome TRAIL-resistance in metastatic castration-resistant prostate cancer (mCRPC).

Funder

National Cancer Institute

Publisher

Public Library of Science (PLoS)

Subject

Multidisciplinary

Cited by 13 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3