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Int J Biol Sci 2022; 18(3):1238-1253. doi:10.7150/ijbs.58784 This issue Cite

Research Paper

Poly (ADP-ribose) polymerase 1 (PARP1) inhibition promotes pulmonary metastasis of osteosarcoma by boosting ezrin phosphorylation

Fangfei Li^1,2,3#✉, Xiaoqiu Wu^1,2,3#, Xuekun Fu^1,4#, Jin Liu^1,2,3, Wangze Song⁵, Gary Guishan Xiao⁵, Aiping Lu^1,2,3,6,7✉, Ge Zhang^1,2,3✉

1. Shum Yiu Foon Sum Bik Chuen Memorial Centre for Cancer and Inflammation Research (CCIR), School of Chinese Medicine, Hong Kong Baptist University, 999077, Hong Kong SAR, China.
2. Law Sau Fai Institute for Advancing Translational Medicine in Bone & Joint Diseases, Hong Kong Baptist University, 999077, Hong Kong SAR, China.
3. Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, 999077, Hong Kong SAR, China.
4. Department of Biology, Southern University of Science and Technology, Shenzhen 518055, China.
5. Department of Pharmacology, School of Chemical Engineering, Dalian University of Technology, 116024, Dalian, Liaoning, China.
6. Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, 100700, Beijing, China.
7. Institute of Arthritis Research, Shanghai Academy of Chinese Medical Sciences, 200032, Shanghai, China.
#These authors contributed equally to this work.

✉ Corresponding authors: Email: zhanggeedu.hk, aipingluedu.hk, fangfeiliedu.hk

Abstract

Due to the large proportion of BRCA deficiency and chromosomal instability in OS patients, poly (ADP-ribose) polymerase inhibitors (PARPi) could be an effective strategy for anti-OS therapy. In two orthotopic OS mouse models, we discovered that although PARPi had inhibitory effect on the growth of the orthotopic OS tumors regardless of BRCA deficiency, the treatment of PARPi essentially aggravated the pulmonary metastasis of OS in both models. A protein playing a crucial role in OS metastasis, ezrin, was identified as an interactive protein for PARP1. The phosphorylation of ezrin was significantly promoted during PARP inhibition. Besides the traditional function of phosphorylated ezrin at plasma membrane, we newly identified its nuclear speckle localization and its function with mRNA export. Ezrin knockdown or phosphorylation inhibition could partially rescue PARPi induced metastasis. Collectively, we unveiled a new mechanism for PARP-involved OS metastasis, which proposed a novel combinational therapy strategy using PARP and ezrin inhibitors for future OS treatment.

Keywords: Osteosarcoma, metastasis, PARP1, ezrin, combination therapy.

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