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

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.

Automated summary

This study revealed that PARP inhibitors have inhibitory effect on orthotopic osteosarcoma tumors, but they exacerbate pulmonary metastasis. Ezrin protein, which plays a crucial role in tumor metastasis, was found to interact with PARP1. Additionally, phosphorylation of ezrin was significantly increased during PARP inhibition, and it was found to have nuclear speckle localization and a function in mRNA export. Knockdown or inhibition of ezrin phosphorylation could partially reverse PARPi-induced metastasis.