PLA2G16 promotes osteosarcoma metastasis and drug resistance via the MAPK pathway

Abstract

The prognosis of metastatic osteosarcoma is dismal and a better understanding of the mechanisms underlying disease progression is essential to improve treatment options and patient outcomes. We previously demonstrated Pla2g16 overexpression in mouse osteosarcoma contributes to metastasis phenotypes and increased expression of PLA2G16 is associated with metastasis and poor prognosis in human tumors. To further examine the mechanisms through which PLA2G16 contributes to human osteosarcoma metastasis and explore the potential of PLA2G16 as a therapeutic target in osteosarcoma, we generated a panel of human osteosarcoma cell lines expressing different levels of PLA2G16. The functional analyses of these cell lines demonstrated high levels of PLA2G16 expression increased osteosarcoma cell migration, invasion, clonogenic survival, and anchorage-independent colony formation. Importantly, this activity was dependent on the phospholipase activity of PLA2G16. Additionally, PLA2G16 overexpression decreased the sensitivity of cells to a panel of chemotherapeutic agents. Analysis of downstream pathways revealed the pro-metastasis functions of PLA2G16 were mediated through the MAPK pathway, as knockdown of PLA2G16 decreased ERK1/2 phosphorylation and pharmacological inhibition of MEK significantly repressed PLA2G16 mediated cell migration and clonogenic survival. Furthermore, PLA2G16 overexpression promoted xenograft tumor growth in vivo, and these tumors exhibit increased ERK1/2 phosphorylation. Lastly, the expression of PLA2G16 is strongly correlated with the increased ERK1/2 phosphorylation in human osteosarcoma samples, and the combined lesions are associated with reduced overall and metastasis-free survival. Collectively, these results demonstrate increased PLA2G16 expression activates the MAPK pathway to enhance osteosarcoma metastasis and may be a novel therapeutic target for these cancers.

ONZIN Upregulation by Mutant p53 Contributes to Osteosarcoma Metastasis Through the CXCL5-MAPK Signaling Pathway

“…These data are in agreement with p53 GOF results in mammary tumor cells, in which multiple genes of the mevalonate pathway are activated by mutant p53 [10]. Additionally, the activated MAPK pathway is strongly associated with osteosarcoma metastasis and poor prognoses [9]. Thus, multiple mechanisms that activate the MAPK pathway may be important for mutant p53 GOF in osteosarcoma.…”

“…To develop a new treatment for osteosarcoma, the anti-tumor effect of the proteasome inhibitor MLN9708/2238 was tested in osteosarcoma cells, where it can inhibit cell growth and induce cell cycle arrest and apoptosis, indicating the proteasome may be a novel biochemical target for osteosarcoma treatment [7] To expore other biomarkers and therapeutic targets for osteosarcoma, we have previously identified more than 200 genes that are differentially expressed between the metastatic osteosarcomas from p53 R172H/+ mice and non-metastatic osteosarcomas from p53 +/-mice. Among these more than 200 genes, we further demonstrated Pla2g16 overexpression induced by mutant p53 contributes to osteosarcoma progression and metastasis [8,9]. It is unclear whether other genes such as Onzin contribute to osteosarcoma metastasis.…”

miR‑142‑5p suppresses proliferation and promotes apoptosis of human osteosarcoma cell line, HOS, by targeting PLA2G16 through the ERK1/2 signaling pathway

“…The underlying mechanism of miR-142 function in mediating ERK phosphorylation has been illustrated and decreased miR-142 expression levels lead to enhanced levels of ERK phosphorylation, contributing to cell differentiation in mouse embryonic stem cells (36,37). It has also been demonstrated that enhanced PLA2G16 expression promotes OS metastasis through activating the MAPK pathway and may be a novel therapeutic target for various types of cancer (38). The findings of the present study indicated that miR-142-5p transfection decreased the phosphorylation of Raf-1/MEK/ERK1/2 proteins in HOS cells, suggesting that miR-142-5p may act by the Raf/MEK/ERK1/2 signaling pathway.…”

Delineation of hypoxia-induced proteome shifts in osteosarcoma cells with different metastatic propensities

“…OS is a malignant neoplasm of the bone having a high propensity for pulmonary metastasis with approximately 20% of patients diagnosed with metastatic tumors and 80% developing metastasis despite standard of care treatment including surgery and chemotherapy 3,4 . Less than 15% of patients with metastatic OS experience 5-year survival rates with current non-targeted treatments, and, over the last three decade there was little improvement in survival rates [5][6][7][8] . Thus, there is an urgent need for new therapeutic strategies aiming to control metastasis in OS.…”