LOX upregulates FAK phosphorylation to promote metastasis in osteosarcoma

Abstract

Osteosarcoma is a malignant bone tumor that commonly occurs in the pediatric population. Despite the use of chemotherapy and surgery, metastasis remains to be the leading cause of death in patients with osteosarcoma. We have previously reported that cytoplasmic mislocalization of p27 is associated with a poor outcome in osteosarcoma. In this study, we further show that lysyl oxidase (LOX) expression was associated with p27 mislocalization. LOX is an enigmatic molecule that acts as a tumor suppressor or a metastatic promoter; however, its role in osteosarcoma is still unclear. Hence, we performed both in vitro and in vivo analyses to dissect the role of LOX in osteosarcoma. The result of our survival analysis indicated that LOX expression significantly correlated with a poor outcome in osteosarcoma with or without controlling for the initial metastasis status (P < 0.05). Functionally, we found that higher LOX expression promoted osteosarcoma cell proliferation, migration, and invasiveness in vitro and produced a higher number of mice with pulmonary metastases in an orthotopic xenograft mouse model. Mechanistically, phospho-FAK was increased in osteosarcoma cells with high LOX expression. Our results further showed that FAK inhibition significantly reduced tumor cell proliferation and migration in vitro as well as LOX-mediated metastasis in mice. Together, our findings suggest that there is a novel link between p27 mislocalization and LOX expression. LOX plays a pivotal role in osteosarcoma metastasis by upregulating FAK phosphorylation. FAK inhibition may constitute a promising therapeutic strategy to reduce the development of metastasis in osteosarcoma with LOX overexpression.