Sulfated alginate oligosaccharide exerts antitumor activity and autophagy induction by inactivating MEK1/ERK/mTOR signaling in a KSR1-dependent manner in osteosarcoma
Zhen Pan,
Xiao-juan Wei,
Shi-jie Li,
Hua Guo,
Zhao-hui Li,
Ke-ke Zhang,
Qian-qian Lyu,
Wei-zhi Liu,
Qing-cheng Yang,
Dong-dong Cheng
Affiliations
Zhen Pan
Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital
Xiao-juan Wei
Institute of Microsurgery on Extremities, Shanghai Jiao Tong University Affiliated Shanghai Sixth People’s Hospital
Shi-jie Li
Department of Orthopaedic Surgery, Yangpu Hospital, Tongji University School of Medicine
Hua Guo
Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital
Zhao-hui Li
Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital
Ke-ke Zhang
MOE Key Laboratory of Marine Genetics and Breeding, College of Marine Life Sciences, Ocean University of China
Qian-qian Lyu
MOE Key Laboratory of Marine Genetics and Breeding, College of Marine Life Sciences, Ocean University of China
Wei-zhi Liu
MOE Key Laboratory of Marine Genetics and Breeding, College of Marine Life Sciences, Ocean University of China
Qing-cheng Yang
Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital
Dong-dong Cheng
Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital
Abstract Alginate oligosaccharide (AOS) has the function to inhibit tumor progression and the sulfated modification can enhance the antitumor activity. To date, the function and mechanism of sulfated AOS (AOS-SO4) in tumors remain largely elusive. We prepared AOS by the enzymatic degradation of alginate, collected AOS-SO4 by sulfating following the canonical procedure. Using these materials, in vitro assays showed that both AOS and AOS-SO4 elicited antitumor effects in osteosarcoma cells. Sulfated modification significantly enhanced the antitumor activity. In addition, AOS-SO4 had obvious effects on cell cycle arrest, apoptosis, and autophagy induction in vitro and in vivo. Mechanistically, we observed that AOS-SO4 treatment triggered proapoptotic autophagy by inhibiting MEK1/ERK/mTOR signaling. The ERK activator reversed AOS-SO4-induced autophagy. More importantly, we found that KSR1 interacted with MEK1 and functioned as a positive regulator of MEK1 protein in osteosarcoma cells. High KSR1 expression was significantly associated with poor survival in osteosarcoma patients. Together, these results suggest that AOS-SO4 has a better antitumor effect in osteosarcoma by inhibiting MEK1/ERK/mTOR signaling, which is KSR1-dependent; thus, AOS-SO4 can be a new potential therapeutic candidate for the treatment of osteosarcoma.
