Dihydrotanshinone I Enhances Cell Adhesion and Inhibits Cell Migration in Osteosarcoma U−2 OS Cells through CD44 and Chemokine Signaling

Abstract

In the screening of novel natural products against cancer using an in vitro cancer cell model, we recently found that tanshinones from a traditional Chinese medicine, the rhizome of Salvia miltiorrhiza Bunge (Danshen), had potent effects on cell proliferation and migration. Especially for human osteosarcoma U−2 OS cells, tanshinones significantly enhanced the cell adherence, implying a possible role in cell adhesion and cell migration inhibition. In this work, therefore, we aimed to provide a new insight into the possible molecule mechanisms of dihydrotanshinone I, which had the strongest effects on cell adhesion among several candidate tanshinones. RNA−sequencing-based transcriptome analysis and several biochemical experiments indicated that there were comprehensive signals involved in dihydrotanshinone I-treated U−2 OS cells, such as cell cycle, DNA replication, thermogenesis, tight junction, oxidative phosphorylation, adherens junction, and focal adhesion. First, dihydrotanshinone I could potently inhibit cell proliferation and induce cell cycle arrest in the G0/G1 phase by downregulating the expression of CDK4, CDK2, cyclin D1, and cyclin E1 and upregulating the expression of p21. Second, it could significantly enhance cell adhesion on cell plates and inhibit cell migration, involving the hyaluronan CD44−mediated CXCL8–PI3K/AKT–FOXO1, IL6–STAT3–P53, and EMT signaling pathways. Thus, the increased expression of CD44 and lengthened protrusions around the cell yielded a significant increase in cell adhesion. In summary, these results suggest that dihydrotanshinone I might be an interesting molecular therapy for enhancing human osteosarcoma U−2 OS cell adhesion and inhibiting cell migration and proliferation.

Identification of microtubule-associated biomarker using machine learning methods in osteonecrosis of the femoral head and osteosarcoma

“…In OS and ONFH, the regulation of cell adhesion may affect the metastatic ability of tumor cells and structure and function of bone tissue [ 34 ]. T cells, a key cell type in the immune system, participate in regulating immune responses and immune tolerance [ [35] , [36] , [37] , [38] , [39] ]. The abnormal differentiation of T cells may be associated with immune imbalance and inflammatory responses in OS and ONFH [ 36 ].…”

PDE1B, a potential biomarker associated with tumor microenvironment and clinical prognostic significance in osteosarcoma

“…Zheng et al identified POGZ as a hub gene in osteosarcoma, related to the cell cycle pathway 33 . Fan et al found that dihydrotanshinone I could regulate osteosarcoma U-2 OS cells' adhesion and migration via chemokine pathways 34 . As for the JAK STAT pathway, Lv et al utilized bioinformatics analyses and firstly www.nature.com/scientificreports/ mined serglycin as a prognostic marker involved with the JAK/STAT pathway 35 .…”

CD44 and its implication in neoplastic diseases

“…A number of studies have also highlighted the effect of CD44 on AKT in relation to cancer cell growth, motility, invasion and stemness. 217 , 218 , 219 Thanee et al. 220 found that silencing CD44 inhibited cholangiocarcinoma progression and aggressiveness, as well as AKT and mTOR phosphorylation.…”

“…A number of studies have also highlighted the effect of CD44 on AKT in relation to cancer cell growth, motility, invasion and stemness. [217][218][219] Thanee et al 220 found that silencing CD44 inhibited cholangiocarcinoma progression and aggressiveness, as well as AKT and mTOR phosphorylation. As demonstrated by GC cell lines and an experimental animal model, chitinase-like protein CHI3L1 binding to CD44v3 was a specific inducer of activation of ERK, AKT, and β-catenin signaling and enhancement of GC transfer.…”

“…A number of studies have also highlighted the effect of CD44 on AKT in relation to cancer cell growth, motility, invasion and stemness 217–219 . Thanee et al 220 .…”