ISSN: 1449-2288International Journal of Biological Sciences
Global reach, higher impact
Int J Biol Sci 2020; 16(2):330-341. doi:10.7150/ijbs.37781 This issue Cite
Research Paper
G721-0282 inhibits cell growth and induces apoptosis in human osteosarcoma through down-regulation of the STAT3 pathway
1. College of Pharmacy and Medical Research Center, Chungbuk National University, Chungbuk 194-31, Republic of Korea
2. Department of Oral and Maxillofacial Pathology, School of Dentistry, Kyung Hee University, Seoul 02453, Republic of Korea.
*Park KR and Yun HM contributed equally to this work as first authors.
Abstract
Osteosarcoma (OS) is considered the most common type of primary malignant bone tumor, which has an urgent need for more effective treatment. Recently, chitinase 3 like 1 (Chi3L1) expression has been found in a variety of cancer cells. However it is not known whether Chi3L1 regulates the STAT3 pathway in OS cells. Herein, we examined the effects of the G721-0282, a ligand of Chi3L1, in vitro and in vivo against OS cells. G721-0282 inhibited the proliferation of OS cells and induced apoptosis. This apoptosis was accompanied by upregulation of apoptotic proteins (PARP and procaspase-3), but downregulation of anti-apoptotic proteins (Survivin and Bcl-2). G721-0282 induced the inactivation of mitogen-activated protein kinases (MAPKs) with a decrease in the phosphorylation of Src and STAT3 in OS cells. Importantly, overexpression of Chi3L1 potentiated the effects of G721-0282, while knockdown of Chi3L1 attenuated the effects of G721-0282. Docking model study also showed that G721-0282 interacted with Chi3L1. In addition, G721-0282 inhibited cell migration, invasion, and colony formation. Furthermore, the anti-tumor effects of G721-0282 were observed in an xenograft in vivo model in association with the reduced expression of Chi3L1, PCNA, Cyclin D1, p-STAT3, as well as the increased expression of Chi3L1 was correlated with the p-STAT3 level in human bone tumor tissues. Taken together, a Chi3L1 ligand, G721-0282 may be an attractive therapeutic strategy for OS, especially in vitro and in vivo anti-proliferative effects against OS cells through the inhibition of the STAT3 pathway, and suggest the potentially therapeutic application of G721-0282 in the treatment of OS.
Keywords: G721-0282, Chi3L1, STAT3, osteosarcoma, Src, MAPK
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