Arsenic sulfide induces apoptosis and autophagy through the activation of ROS/JNK and suppression of Akt/mTOR signaling pathways in osteosarcoma

Gangyang Wang; Tao Zhang; Wei Sun; Hongsheng Wang; Fei Yin; Zhuoying Wang; Dongqing Zuo; Mengxiong Sun; Zifei Zhou; Binhui Lin; Jing Xu; Yingqi Hua; Haoqing Li; Zhengdong Cai

doi:10.1016/j.freeradbiomed.2017.02.015

Arsenic sulfide induces apoptosis and autophagy through the activation of ROS/JNK and suppression of Akt/mTOR signaling pathways in osteosarcoma

Free Radic Biol Med. 2017 May:106:24-37. doi: 10.1016/j.freeradbiomed.2017.02.015. Epub 2017 Feb 7.

Authors

Gangyang Wang¹, Tao Zhang², Wei Sun³, Hongsheng Wang⁴, Fei Yin⁵, Zhuoying Wang⁶, Dongqing Zuo⁷, Mengxiong Sun⁸, Zifei Zhou⁹, Binhui Lin¹⁰, Jing Xu¹¹, Yingqi Hua¹², Haoqing Li¹³, Zhengdong Cai¹⁴

Affiliations

¹ Department of Orthopaedics, Shanghai Bone Tumor Institute, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: [email protected].
² Department of Orthopaedics, Shanghai Bone Tumor Institute, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: [email protected].
³ Department of Orthopaedics, Shanghai Bone Tumor Institute, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: [email protected].
⁴ Department of Orthopaedics, Shanghai Bone Tumor Institute, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Orthopaedics, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China. Electronic address: [email protected].
⁵ Department of Orthopaedics, Shanghai Bone Tumor Institute, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: [email protected].
⁶ Department of Orthopaedics, Shanghai Bone Tumor Institute, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: [email protected].
⁷ Department of Orthopaedics, Shanghai Bone Tumor Institute, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Orthopaedics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China. Electronic address: [email protected].
⁸ Department of Orthopaedics, Shanghai Bone Tumor Institute, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: [email protected].
⁹ Department of Orthopaedics, Shanghai Bone Tumor Institute, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Orthopaedics, Shanghai East Hospital, Tongji University, Shanghai, China. Electronic address: [email protected].
¹⁰ Department of Orthopaedics, Shanghai Bone Tumor Institute, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: [email protected].
¹¹ Department of Orthopaedics, Shanghai Bone Tumor Institute, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: [email protected].
¹² Department of Orthopaedics, Shanghai Bone Tumor Institute, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: [email protected].
¹³ Department of Orthopaedics, Shanghai Bone Tumor Institute, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: [email protected].
¹⁴ Department of Orthopaedics, Shanghai Bone Tumor Institute, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: [email protected].

PMID: 28188923
DOI: 10.1016/j.freeradbiomed.2017.02.015

Abstract

Osteosarcoma is a common primary malignant bone tumor, the cure rate of which has stagnated over the past 25-30 years. Arsenic sulfide (As₂S₂), the main active ingredient of the traditional Chinese medicine realgar, has been proved to have antitumor efficacy in several tumor types including acute promyelocytic leukemia, gastric cancer and colon cancer. Here, we investigated the efficacy and mechanism of As₂S₂ in osteosarcoma both in vitro and in vivo. In this study, we demonstrated that As₂S₂ potently suppressed cell proliferation by inducing G2/M phase arrest in various osteosarcoma cell lines. Also, treatment with As₂S₂ induced apoptosis and autophagy in osteosarcoma cells. The apoptosis induction was related to PARP cleavage and activation of caspase-3, -8, -9. As₂S₂ was demonstrated to induce autophagy as evidenced by formation of autophagosome and accumulation of LC3II. Further studies showed that As₂S₂-induced apoptosis and autophagy could be significantly attenuated by ROS scavenger and JNK inhibitor. Moreover, we found that As₂S₂ inhibited Akt/mTOR signaling pathway, and suppressing Akt and mTOR kinases activity can increase As₂S₂-induced apoptosis and autophagy. Finally, As₂S₂in vivo suppressed tumor growth with few side effects. In summary, our results revealed that As₂S₂ induced G2/M phase arrest, apoptosis, and autophagy via activing ROS/JNK and blocking Akt/mTOR signaling pathway in human osteosarcoma cells. Arsenic sulfide may be a potential clinical antitumor drugs targeting osteosarcoma.

Keywords: Apoptosis; Arsenic sulfide; Autophagy; Cell cycle; Osteosarcoma.

MeSH terms

Animals
Apoptosis / drug effects
Arsenicals / administration & dosage*
Autophagy / drug effects
Caspases / biosynthesis
Cell Line, Tumor
Cell Proliferation / drug effects
Gene Expression Regulation, Neoplastic / drug effects
Humans
MAP Kinase Signaling System / drug effects
Medicine, Chinese Traditional
Mice
Oncogene Protein v-akt / genetics*
Osteosarcoma / drug therapy*
Osteosarcoma / genetics
Osteosarcoma / pathology
Reactive Oxygen Species / metabolism
Signal Transduction
Sulfides / administration & dosage*
TOR Serine-Threonine Kinases / genetics*
Xenograft Model Antitumor Assays

Substances

Arsenicals
Reactive Oxygen Species
Sulfides
arsenic trisulfide
arsenic disulfide
MTOR protein, human
Oncogene Protein v-akt
TOR Serine-Threonine Kinases
Caspases