α-Mangostin Induces Apoptosis in Human Osteosarcoma Cells Through ROS-Mediated Endoplasmic Reticulum Stress via the
Shengsen Yang1, Fei Zhou2, Yi Dong1
1Departments of Spine Orthopedics, General Hospital of Ningxia Medical University, Yinchuan, China.
Abstract:
α-mangostin has been confirmed to promote the apoptosis of MG-63 cells, but its specific pro-apoptosis mechanism in osteosarcoma (OS) remains further investigation. Here, we demonstrated that α-mangostin restrained the viability of OS cells (143B and Saos-2), but had little effect on the growth of normal human osteoblast. α-mangostin increased OS cell apoptosis by activating the caspase-3/8 cascade. Besides, α-mangostin induced endoplasmic reticulum (ER) stress and restrained the Wnt/β-catenin pathway activity. 4PBA (an ER stress inhibitor) or LiCl (an effective Wnt activator) treatment effectively hindered α-mangostin-induced apoptosis and the caspase-3/8 cascade. Furthermore, we also found that α-mangostin induced ER stress by promoting ROS production. And ER stress-mediated apoptosis caused by ROS accumulation depended on the inactivation of Wnt/β-catenin pathway. In addition, α-mangostin significantly hindered the growth of xenograft tumors, induced the expression of ER stress marker proteins and activation of the caspase-3/8 cascade, and restrained the Wnt/β-catenin signaling in vivo. In short, ROS-mediated ER stress was involved in α-mangostin triggered apoptosis, which might depended on Wnt/β-catenin signaling inactivation.
Insights
Alpha-mangostin promotes osteosarcoma cell death by inducing reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress, which inactivates the Wnt/β-catenin pathway. This mechanism was confirmed in both cell cultures and animal models.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Osteosarcoma (OS) is a primary bone malignancy with limited treatment options.
- Alpha-mangostin exhibits anti-cancer properties, but its precise mechanism in OS requires elucidation.
- Previous studies suggest α-mangostin induces apoptosis in MG-63 cells.
Purpose of the Study:
- To investigate the specific pro-apoptosis mechanism of α-mangostin in osteosarcoma (OS) cells.
- To determine the role of endoplasmic reticulum (ER) stress and Wnt/β-catenin signaling in α-mangostin-induced apoptosis.
- To evaluate the anti-tumor efficacy of α-mangostin in vivo.
Main Methods:
- Cell viability assays on OS cells (143B, Saos-2) and normal osteoblasts.
- Western blotting to assess apoptosis markers (caspase-3/8), ER stress markers, and Wnt/β-catenin pathway proteins.
- Reactive oxygen species (ROS) detection.
- In vivo xenograft tumor models in mice.
Main Results:
- α-mangostin inhibited OS cell viability and induced apoptosis via caspase-3/8 activation.
- α-mangostin triggered endoplasmic reticulum (ER) stress by promoting ROS production.
- α-mangostin suppressed Wnt/β-catenin pathway activity; ER stress inhibition or Wnt activation blocked apoptosis.
- α-mangostin reduced tumor growth in vivo, consistent with ER stress induction and Wnt/β-catenin pathway inhibition.
Conclusions:
- α-mangostin induces osteosarcoma cell apoptosis through a mechanism involving ROS-mediated ER stress.
- The observed apoptosis is dependent on the inactivation of the Wnt/β-catenin signaling pathway.
- α-mangostin demonstrates potential as an anti-cancer therapeutic agent for osteosarcoma.
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