ANGPTL4 negatively regulates the progression of osteosarcoma by remodeling branched-chain amino acid metabolism

Angiopoietin-like-4 (ANGPTL4), a secreted glycoprotein that is mainly known as a regulator in lipid metabolism, now, is also indicated to be involved in the regulation of cancer progression and metastasis. However, little is known about not only biological functions, but also underlying mechanism of ANGPTL4 in the progression of osteosarcoma (OS). Here, we discovered that ANGPTL4 is downregulated in OS, and is associated with branched-chain amino acid (BCAA) metabolism. The BCAAs (valine, leucine, and isoleucine) are essential amino acids that play an important role in metabolic regulation. Aberrant BCAA metabolism is also found in various cancers and is associated with tumor progression, including proliferation, invasion, and metastasis. In this study, we indicated that the negative relation between the expression of ANGPTL4 and BCAA catabolism in OS samples and cell lines. The knockdown of ANGPTL4 in OS cells resulted in the accumulation of BCAAs, which in turn activated the mTOR signaling pathway, enhancing OS cell proliferation. Thus, reduced expression of ANGPTL4 is associated with the progression of OS. Taken together, our results demonstrated that the ANGPTL4/BCAA/mTOR axis is an important pathway in OS progression and may be a potential therapeutic target to slow OS progression.