Notoginsenoside R1 counteracts mesenchymal stem cell-evoked oncogenesis and doxorubicin resistance in osteosarcoma cells
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PRECLINICAL STUDIES
Notoginsenoside R1 counteracts mesenchymal stem cell-evoked oncogenesis and doxorubicin resistance in osteosarcoma cells by blocking IL-6 secretion-induced JAK2/STAT3 signaling Minan Lu 1,2 & Kegong Xie 2 & Xianzhe Lu 2 & Lu Lu 2 & Yu Shi 2 & Yujin Tang 1,2 Received: 9 September 2020 / Accepted: 25 October 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Summary Tumor microenvironment is a critical participant in the initiation, progression and drug resistance of carcinomas, including osteosarcoma. Notoginsenoside R1 (NGR1) is a proverbial active ingredient of the traditional Chinese medicine Panax notoginseng (PN) and possess undeniable roles in several cancers. Nevertheless, its function in osteosarcoma and tumor microenvironment remains elusive. In the current study, exposure to NGR1 dose-dependently inhibited osteosarcoma cell viability and migration, and induced apoptosis. Furthermore, osteosarcoma cells that were incubated with conditioned medium (CM) from bone marrow mesenchymal stem cells (BMSCs) exhibited greater proliferation, migration capacity and MMP-2 and MMP-9 expression relative to control cells, which was reversed when BMSCs were treated with NGR1. Notably, administration with NGR1 antagonized CM-evoked doxorubicin resistance in osteosarcoma cells by decreasing cell viability and increasing cell apoptosis and caspase-3/9 activity. Mechanically, NGR1 suppressed IL-6 secretion from BMSCs, as well as the subsequent activation of the JAK2/STAT3 signaling in osteosarcoma cells. In addition, blocking the JAK2 pathway by its antagonist AG490 reversed CM-induced osteosarcoma cell proliferation, migration and doxorubicin resistance. Moreover, exogenous supplementation with IL-6 engendered not only the reactivation of the JAK2/STAT3 signaling but also muted NGR1-mediated efficacy against osteosarcoma cell malignancy and doxorubicin resistance. Collectively, NGR1 may directly restrain osteosarcoma cell growth and migration, or indirectly antagonize MSC-evoked malignancy and drug resistance by interdicting IL-6 secretionevoked activation of the JAK2/STAT3 pathway. Consequently, the current study may highlight a promising therapeutic strategy against osteosarcoma by regulating tumor cells and the tumor microenvironment. Keywords Osteosarcoma . Tumor microenvironment . MSCs . NGR1 . Cell proliferation and migration . Drug resistance
Introduction Osteosarcoma (OS) is the most common primary malignant bone sarcoma with highly invasive, and predominantly prevails in children, adolescents and young adults. OS has been found to be the third most common carcinoma in adolescence [1]. Over the past few decades, newly diagnosed patients with OS have usually benefitted from conventional treatment options,
* Yujin Tang [email protected] 1
Department of Orthopedic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou 510630, Guangdong, China
2
Department of Orthopedic Surgery, The Affiliated Hospital of Youjiang Medical University for Nationalities, B
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