Tomatidine Represses Invasion and Migration of Human Osteosarcoma U2OS and HOS Cells by Suppression of Presenilin 1 and c-Raf-MEK-ERK Pathway.

Min-Hong Hsieh,Horng-Rong Chang,Renn-Chia Lin,Yi-Hsien Hsieh,Shun-Fa Yang,Ko-Hsiu Lu,Jia-Sin Yang

doi:10.3390/molecules25020326

Min-Hong Hsieh, Horng-Rong Chang + Show 5 more

Open Access

https://doi.org/10.3390/molecules25020326

Copy DOI

Abstract

Osteosarcoma, which is the most prevalent malignant bone tumor, is responsible for the great majority of bone cancer-associated deaths because of its highly metastatic potential. Although tomatidine is suggested to serve as a chemosensitizer in multidrug-resistant tumors, the anti-metastatic effect of tomatidine in osteosarcoma is still unknown. Here, we tested the hypothesis that tomatidine suppresses migration and invasion, features that are associated with metastatic process in human osteosarcoma cells and also investigate its underlying pathway. Tomatidine, up to 100 μM, without cytotoxicity, inhibited the invasion and migration capabilities of human osteosarcoma U2OS and HOS cells and repressed presenilin 1 (PS-1) expression of U2OS cells. After the knockdown of PS-1, U2OS and HOS cells’ biological behaviors of cellular invasion and migratory potential were significantly reduced. While tomatidine significantly decreased the phosphorylation of c-Raf, mitogen/extracellular signal-regulated kinase (MEK), and extracellular signal-regulated protein kinase (ERK)1/2 in U2OS cells, no obvious influences on p-Jun N-terminal kinase, p38, and Akt, including their phosphorylation, were observed. In ERK 1 silencing U2 OS cells, tomatidine further enhanced the decrease of their migratory potential and invasive activities. We conclude that both PS-1 derived from U2OS and HOS cells and the c-Raf–MEK–ERK pathway contribute to cellular invasion and migration and tomatidine could inhibit the phenomenons. These findings indicate that tomatidine might be a potential candidate for anti-metastasis treatment of human osteosarcoma.

Highlights

Osteosarcoma, which mainly arises from the metaphysis of long bones, is the most prevalent malignant bone tumor with a peak of incidence at 10–15 years and the second incidence peak in older adulthood [1,2]
Through a further analysis of Mitogen-activated protein kinases (MAPKs) and the phosphatidylinositide-3 kinase (PI3K) pathways, tomatidine decreased the phosphorylation of c-Raf, mitogen/extracellular signal-regulated kinase (MEK), and extracellular signal-regulated protein kinase (ERK) 1/2 in U2OS and HOS cells, whereas there was no evident influence on Jun N-terminal kinase (JNK) 1/2, p38, and Akt, and their phosphorylation
We found that tomatidine represses presenilin 1 (PS-1) to inhibit the biological behaviors of migration and invasion in U2OS and HOS cells, which indicates that PS-1 might represent a novel prognostic biomarker and a potential therapeutic target for anti-metastasis treatment of osteosarcoma

Summary

Introduction

Osteosarcoma, which mainly arises from the metaphysis of long bones, is the most prevalent malignant bone tumor with a peak of incidence at 10–15 years and the second incidence peak in older adulthood [1,2]. The potent metastatic transfer to the lungs is still responsible for most treatment failures and it is accountable for one of the most lethal pediatric malignancies. Cancer metastasis involves highly coordinated, sequential, and complex pathways that are collectively termed the metastasis cascade [5,6] These pathways include the detachment of cancer cells, epithelial-mesenchymal transition (EMT), degradation of the extracellular matrix (ECM), invasion, and migration, penetrating through the basement membrane of blood and lymph vessels, intravasation, traveling through lymph fluid and bloodstream, adhering to endothelial cells of vessels, extravasation, mesenchymal-epithelial transition, and re-establishment of growth at a distant site [7,8]

Methods

Results

Discussion

Conclusion