Gadolinium chloride elicits apoptosis in human osteosarcoma U-2 OS cells through extrinsic signaling, intrinsic pathway and endoplasmic reticulum stress

Tsai,Yuh-Feng; Huang,Ching-Wen; Chiang,Jo-Hua; Tsai,Fuu-Jen; Hsu,Yuan-Man; Lu,Chi-Cheng; Hsiao,Chen-Yu; Yang,Jai-Sing

doi:10.3892/or.2016.5174

Gadolinium chloride elicits apoptosis in human osteosarcoma U-2 OS cells through extrinsic signaling, intrinsic pathway and endoplasmic reticulum stress

Authors:
- Yuh-Feng Tsai
- Ching-Wen Huang
- Jo-Hua Chiang
- Fuu-Jen Tsai
- Yuan-Man Hsu
- Chi-Cheng Lu
- Chen-Yu Hsiao
- Jai-Sing Yang
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Affiliations: Department of Diagnostic Radiology, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan, R.O.C., Department of Nursing, Chung-Jen Junior College of Nursing, Health Sciences and Management, Chiayi County, Taichung, Taiwan, R.O.C., Human Genetic Center, China Medical University Hospital, Taichung, Taiwan, R.O.C., Department of Biological Science and Technology, China Medical University, Taichung, Taiwan, R.O.C., School of Nutrition and Health Sciences, Taipei Medical University, Taipei, Taiwan, R.O.C., Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan, R.O.C.
Published online on: October 14, 2016 https://doi.org/10.3892/or.2016.5174
Pages: 3421-3426

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Abstract

Gadolinium (Gd) compounds are important as magnetic resonance imaging (MRI) contrast agents, and are potential anticancer agents. However, no report has shown the effect of gadolinium chloride (GdCl3) on osteosarcoma in vitro. The present study investigated the apoptotic mechanism of GdCl3 on human osteosarcoma U-2 OS cells. Our results indicated that GdCl3 significantly reduced cell viability of U-2 OS cells in a concentration-dependent manner. GdCl3 led to apoptotic cell shrinkage and DNA fragmentation in U-2 OS cells as revealed by morphologic changes and TUNEL staining. Colorimetric assay analyses also showed that activities of caspase-3, caspase-8, caspase-9 and caspase-4 occurred in GdCl3-treated U-2 OS cells. Pretreatment of cells with pan-caspase inhibitor (Z-VAD-FMK) and specific inhibitors of caspase-3/-8/-9 significantly reduced cell death caused by GdCl3. The increase of cytoplasmic Ca2+ level, ROS production and the decrease of mitochondria membrane potential (ΔΨm) were observed by flow cytometric analysis in U-2 OS cells after GdCl3 exposure. Western blot analyses demonstrated that the levels of Fas, FasL, cytochrome c, Apaf-1, GADD153 and GRP78 were upregulated in GdCl3-treated U-2 OS cells. In conclusion, death receptor, mitochondria-dependent and endoplasmic reticulum (ER) stress pathways contribute to GdCl3-induced apoptosis in U-2 OS cells. GdCl3 might have potential to be used in treatment of osteosarcoma patients.

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