A c-Met Inhibitor Suppresses Osteosarcoma Progression via the ERK1/2 Pathway in Human Osteosarcoma Cells

Weijie Chen; Su Wu; Yang Huang; Tingting Zhang; Hao Dong; Xing Zheng; Tao Chen; Xiaokang Gong; Gang Liu; Xing Zhao

doi:10.2147/OTT.S317122

A c-Met Inhibitor Suppresses Osteosarcoma Progression via the ERK1/2 Pathway in Human Osteosarcoma Cells

Onco Targets Ther. 2021 Sep 10:14:4791-4804. doi: 10.2147/OTT.S317122. eCollection 2021.

Authors

Weijie Chen^#^{1

2

3}, Su Wu^#⁴, Yang Huang^#³, Tingting Zhang⁵, Hao Dong⁶, Xing Zheng³, Tao Chen³, Xiaokang Gong³, Gang Liu^{1

2}, Xing Zhao¹

Affiliations

¹ Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, HangZhou, People's Republic of China.
² Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, HangZhou, People's Republic of China.
³ Department of Orthopedics, Taizhou Municipal Hospital, Taizhou, People's Republic of China.
⁴ Department of Orthopedics, The Third People's Hospital of JingDeZhen, JingDeZhen, People's Republic of China.
⁵ Taizhou Public Security Supervision Hospital, Taizhou Municipal Hospital, Taizhou, People's Republic of China.
⁶ Department of Gastrointestinal Surgery, Taizhou Municipal Hospital, Taizhou, People's Republic of China.

^# Contributed equally.

Abstract

Introduction: Osteosarcoma is the most common primary malignancy of the bone among adolescents and children. Despite intensive chemotherapy and aggressive surgery, the 5-year survival rate of osteosarcoma still falls under 70%, mainly due to its tendency to metastasize and to develop drug resistance. Therefore, new treatments for osteosarcoma are urgently needed. HGF/c-Met signaling pathway, when dysregulated, is involved in the onset, progression and metastasis of various cancers, making the HGF/c-Met axis a promising therapeutic target.

Methods: In this study, we found Met to be a cancer-promoting gene in osteosarcoma as well, and aimed to investigate the role of a c-met inhibitor (PHA-665752) in osteosarcoma. For this purpose, two human osteosarcoma cell lines (143B and U2OS) were introduced in this study and treated with PHA-665752. CCK8 cell proliferation assay was performed to obtain the IC₅₀ value of PHA-665752 for 143B and U2OS. After that, colony formation assay, transwell migration and invasion assay and wound-healing assay were performed. Furthermore, a tumor-transplanted mouse model was used for in vivo experiments.

Results: Our results showed that PHA-665752 could suppress osteosarcoma progression, promote apoptosis and inhibit proliferation of human osteosarcoma cells. Moreover, we found ERK1/2 pathway to be an important mediator underlying the osteosarcoma-suppressing function of PHA-665752. LY3214996, a highly selective inhibitor of the ERK1/2 pathway, was able to antagonize the effects of PHA-665752 in osteosarcoma. Finally, in vivo experiments indicated that PHA-665752 suppressed tumor growth in a tumor-transplanted mouse model.

Conclusion: Taken together, Met provided a druggable target for osteosarcoma and PHA-665752 is a promising candidate for anti-osteosarcoma treatments.

Keywords: ERK signaling; LY3214996; Met; PHA-665752; osteosarcoma.

Grants and funding

This study was sponsored by Innovative Talents Support Plan Program of Zhejiang Province (2020383422). No benefits in any form have been or will be received from a commercial party related directly or indirectly to the subject of this manuscript.