Verteporfin Inhibits the Progression of Spontaneous Osteosarcoma Caused by Trp53 and Rb1 Deficiency in Ctsk-Expressing Cells via Impeding Hippo Pathway

Author:

Li Yang,Yang Shuting,Yang ShuyingORCID

Abstract

Osteosarcoma is the most common primary malignancy of bone in children and adolescents. Others and our previous studies have shown that Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) as core components of the Hippo pathway are crucial regulators of osteosarcoma formation and progression. Recent studies demonstrated that verteporfin (VP) is an inhibitor of YAP/TAZ signaling in xenograft osteosarcoma. However, whether VP can inhibit primary osteosarcoma in mice is unknown. Mutations of Trp53 and Rb1 occur in approximately 50~70% of human osteosarcoma. In this study, we successfully generated the Ctsk-Cre;Trp53f/f/Rb1f/f mice in which Trp53/Rb1 was ablated in Ctsk-expressing cells and found that Ctsk-Cre;Trp53f/f/Rb1f/f mice spontaneously developed osteosarcoma with increased expansive osteoid lesions in the cortical bone with aging. Loss of Trp53/Rb1 in Ctsk-expressing cells significantly promoted the expression and nuclear translocation of YAP/TAZ. Micro-CT results showed that inhibition of YAP/TAZ by VP delays osteosarcoma progression and protected against bone erosion in Ctsk-Cre;Trp53f/f/Rb1f/f mice. Importantly, the Kaplan–Meier survival curves displayed a significantly longer survival rate after VP treatment in Ctsk-Cre;Trp53f/f/Rb1f/f mice compared to non-injected groups. In vitro studies further showed that VP inhibited the proliferation, migration and invasion in Trp53/Rb1-mutant Ctsk-expressing cells. Moreover, the results from promoter luciferase activity analysis showed that the transcriptional activity of YAP/TAZ was significantly increased in osteosarcoma tissue from Ctsk-Cre;Trp53f/f/Rb1f/f mice, which was attenuated by VP treatment. Overall, these findings suggest that targeting Hippo pathway by VP may be a potential therapeutic strategy for osteosarcoma.

Funder

National Institute on Aging

National Institute of Arthritis and Musculoskeletal and Skin Diseases

Publisher

MDPI AG

Subject

General Medicine

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