{"title":"Targeted Inhibition of p21 Promotes the Growth of Breast Cancer Cells and Impairs the Tumor-Killing Effect of the Vaccinia Virus.","authors":"Xiaoyuan Jia, Yujia Zhao, Qiang Li, Xiaming Lu, Xiaoyan Wang, Hui Wang, Ziyi Shi, Yipeng Xu, Biao Huang, Fang Huang, Yigang Wang","doi":"10.4048/jbc.2024.0063","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>Vaccinia virus is widely used as an oncolytic agent for human cancer therapy, and several versions of vaccinia virus have demonstrated robust antitumor effects in breast cancer. Most vaccinia viruses are modified by thymidine kinase (TK) deletion. The function of the cyclin-dependent kinase inhibitor p21 in breast cancer remains controversial. We explored the impact of p21 gene knockdown (KD) on breast cancer cells and whether p21 KD interferes with the antitumor effect of TK-negative vaccinia virus.</p><p><strong>Methods: </strong>p21 KD MDA-MB-231 and p21 KD MCF-7 cells were prepared, and cell proliferation and migration rates were evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and scratch healing assays. The tumor growth of xenografts originating from p21KD MDA-MB-231 cells and control cells was compared in a mouse model. The colony formation and sphere-forming abilities of p21 KD breast cancer cells were also determined using low-melting agarose and serum-free culture. The tumor-killing effect of the vaccinia virus was determined in breast cancer cells and mouse models using an MTT assay and tumor cell xenografts.</p><p><strong>Results: </strong>p21 KD increased the growth and migration of MDA-MB-231 and MCF-7 cells and promoted the cell growth of MDA-MB-231 cells in mice, while decreasing the colony formation and sphere formation abilities. Expression of TK was reduced in p21 KD MDA-MB-231 cells. Oncolytic effects of both wild-type and TK-deleted vaccinia viruses were attenuated in p21KD MDA-MB-231 cells. The tumor-killing effect of TK-deleted vaccinia virus was also weakened in xenografted mice bearing p21 KD MDA-MB-231 cells.</p><p><strong>Conclusion: </strong>Targeted inhibition of p21 accelerates the proliferation and migration of breast cancer cells and impairs the tumor-killing effect of vaccinia virus, suggesting that p21 levels in cancer cells interfere with vaccinia virus oncolytic therapy.</p>","PeriodicalId":15206,"journal":{"name":"Journal of Breast Cancer","volume":" ","pages":"293-304"},"PeriodicalIF":2.2000,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11543277/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Breast Cancer","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.4048/jbc.2024.0063","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/9/2 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Purpose: Vaccinia virus is widely used as an oncolytic agent for human cancer therapy, and several versions of vaccinia virus have demonstrated robust antitumor effects in breast cancer. Most vaccinia viruses are modified by thymidine kinase (TK) deletion. The function of the cyclin-dependent kinase inhibitor p21 in breast cancer remains controversial. We explored the impact of p21 gene knockdown (KD) on breast cancer cells and whether p21 KD interferes with the antitumor effect of TK-negative vaccinia virus.
Methods: p21 KD MDA-MB-231 and p21 KD MCF-7 cells were prepared, and cell proliferation and migration rates were evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and scratch healing assays. The tumor growth of xenografts originating from p21KD MDA-MB-231 cells and control cells was compared in a mouse model. The colony formation and sphere-forming abilities of p21 KD breast cancer cells were also determined using low-melting agarose and serum-free culture. The tumor-killing effect of the vaccinia virus was determined in breast cancer cells and mouse models using an MTT assay and tumor cell xenografts.
Results: p21 KD increased the growth and migration of MDA-MB-231 and MCF-7 cells and promoted the cell growth of MDA-MB-231 cells in mice, while decreasing the colony formation and sphere formation abilities. Expression of TK was reduced in p21 KD MDA-MB-231 cells. Oncolytic effects of both wild-type and TK-deleted vaccinia viruses were attenuated in p21KD MDA-MB-231 cells. The tumor-killing effect of TK-deleted vaccinia virus was also weakened in xenografted mice bearing p21 KD MDA-MB-231 cells.
Conclusion: Targeted inhibition of p21 accelerates the proliferation and migration of breast cancer cells and impairs the tumor-killing effect of vaccinia virus, suggesting that p21 levels in cancer cells interfere with vaccinia virus oncolytic therapy.
期刊介绍:
The Journal of Breast Cancer (abbreviated as ''J Breast Cancer'') is the official journal of the Korean Breast Cancer Society, which is issued quarterly in the last day of March, June, September, and December each year since 1998. All the contents of the Journal is available online at the official journal website (http://ejbc.kr) under open access policy. The journal aims to provide a forum for the academic communication between medical doctors, basic science researchers, and health care professionals to be interested in breast cancer. To get this aim, we publish original investigations, review articles, brief communications including case reports, editorial opinions on the topics of importance to breast cancer, and welcome new research findings and epidemiological studies, especially when they contain a regional data to grab the international reader''s interest. Although the journal is mainly dealing with the issues of breast cancer, rare cases among benign breast diseases or evidence-based scientifically written articles providing useful information for clinical practice can be published as well.