G721-0282 inhibits cell growth and induces apoptosis in human osteosarcoma through down-regulation of the STAT3 pathway.

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.

SUBMITTER: Park KR 

PROVIDER: S-EPMC6949149 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature