Targeting BMP9-Promoted Human Osteosarcoma Growth by Inactivation of Notch Signaling

Title:Targeting BMP9-Promoted Human Osteosarcoma Growth by Inactivation of Notch Signaling

Volume: 14 Issue: 3

Author(s): Hongmei Zhang, Zhong-Liang Deng, Tong-Chuan He, Rex C. Haydon, Hue H. Luu, Youlin Deng, Jixing Ye, Zhonglin Zhang, Wei Liu, Zhengjian Yan, Qian Zhang, Junhui Zhang, Zhan Liao, Guolin Zhou, Ruidong Li, Fang Deng, Sheng Wen, Xian Chen, Guoxin Nan, Ningning Wu, Ning Wang, Hongyu Zhang, Yang Wang, Liangjun Yin, Wei Shui, Jing Cui and Wenwen Zhang

Affiliation:

Keywords: BMP9, bone tumorigenesis, notch signaling, osteogenesis, osteosarcoma, soft tissue tumors.

Abstract: Osteosarcoma (OS) is the most common primary malignancy of bone and is usually associated with poor prognosis due to its high incidence of metastasis and chemoresistance. Molecular pathogenesis of OS is poorly understood. We previously showed that OS cells are refractory to BMP9-induced osteogenesis and respond favorably to proliferation and tumor growth. Here we investigate if Notch signaling mediates the BMP9-promoted cell proliferation and tumor growth of human osteosarcoma (OS). We find that the expression of Notch1, Notch2, Notch3, DLL1, JAG1 and JAG2 is readily detected in most of the tested OS cell lines. BMP9-promoted OS cell proliferation, migration, and cell cycle S/G2 progression are effectively inhibited by a dominant-negative mutant of Notch1 (dnNotch1) or the γ-secretase inhibitor Compound E (ComE). Furthermore, BMP9-promoted tumor growth and osteolytic lesions in vivo are significantly inhibited by dnNotch1. BMP9 up-regulates the expression of Notch1, Notch3, DLL1, and JAG1 in OS cells. Accordingly, BMP9 stimulation induces a nuclear accumulation of NICD, which is blocked by ComE. Our results demonstrate that BMP9-promoted OS proliferation and tumor growth is at least in part mediated by Notch signaling, suggesting that osteogenic BMPs may function as upstream regulators of Notch signaling in OS tumorigenesis. Thus, pharmacologic intervention of Notch signaling may be explored as a new therapeutic strategy for human OS tumors.

Cite this article as:

Zhang Hongmei, Deng Zhong-Liang, He Tong-Chuan, Haydon C. Rex, Luu H. Hue, Deng Youlin, Ye Jixing, Zhang Zhonglin, Liu Wei, Yan Zhengjian, Zhang Qian, Zhang Junhui, Liao Zhan, Zhou Guolin, Li Ruidong, Deng Fang, Wen Sheng, Chen Xian, Nan Guoxin, Wu Ningning, Wang Ning, Zhang Hongyu, Wang Yang, Yin Liangjun, Shui Wei, Cui Jing and Zhang Wenwen, Targeting BMP9-Promoted Human Osteosarcoma Growth by Inactivation of Notch Signaling, Current Cancer Drug Targets 2014; 14 (3) . https://dx.doi.org/10.2174/1568009614666140305105805