ISSN: 1449-2288International Journal of Biological Sciences
Global reach, higher impact
Int J Biol Sci 2023; 19(2):537-551. doi:10.7150/ijbs.69541 This issue Cite
Research Paper
Ebastine exerts antitumor activity and induces autophagy by activating AMPK/ULK1 signaling in an IPMK-dependent manner in osteosarcoma
1. Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
2. Department of Orthopaedic Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai, 200090, China.
#Authors share co-first authorship.
Abstract
Numerous studies have confirmed that in addition to interfering with the tumor inflammatory environment, anti-inflammatory agents can directly increase apoptosis and sensitivity to conventional therapies and decrease invasion and metastasis, making them useful candidates for cancer therapy. Here, we first used high-throughput screening and had screened one compound candidate, ebastine (a H1-histamine receptor antagonist), for osteosarcoma therapy. Cell viability assays, colony formation assays, wound healing assays, and Transwell assays demonstrated that ebastine elicited antitumor effects in osteosarcoma cells. In addition, ebastine treatment exerted obvious effects on cell cycle arrest, metastasis inhibition, apoptosis and autophagy induction both in vitro and in vivo. Mechanistically, we observed that ebastine treatment triggered proapoptotic autophagy by activating AMPK/ULK1 signaling in osteosarcoma cells. Treatment with the AMPK inhibitor dorsomorphin reversed ebastine-induced apoptosis and autophagy. More importantly, we found that IPMK interacted with AMPK and functioned as a positive regulator of AMPK protein in osteosarcoma cells. A rescue study showed that the induction of autophagy and activation of the AMPK/ULK1 signaling pathway by ebastine treatment were reversed by IPMK knockdown, indicating that the activity of ebastine was IPMK dependent. We provide experimental evidence demonstrating that ebastine has antitumor activity in osteosarcoma and promotes autophagy by activating the AMPK/ULK1 signaling pathway, which is IPMK dependent. Our results provide insight into the clinical application potential of ebastine, which may represent a new potential therapeutic candidate for the treatment of osteosarcoma.
Keywords: Ebastine, osteosarcoma, autophagy, IPMK, AMPK/ULK1 pathway
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