Significance of lysil oxidase-like 2 (LOXL2) expression in hepatocellular carcinoma

Abstract

RT-PCR. LPA variant binding affinities to LPARs was performed using commercially available cell based LPAR agonist assays. LPAR inhibitors were identified by 3D computational docking of 1.2 million compounds against the active site of the LPA biosynthetic enzyme, autotaxin. LPAR antagonism was determined using commercially available cell based LPAR antagonist assays. Results: LPAR2 and LPAR3 were the main hepatic LPARs. Hepatic LPA2 and LPA3 expression was greater in cirrhotic livers with HCC when compared to livers without HCC. LPAR2 and LPAR3 selectively bound 18:2LPA (RC50 1.6 mM) in preference to other LPA variants (e.g. 20:4LPA RC50 2.4ï -M). Six compounds were identified with LPAR IC50 <10 nM. Conclusion: HCC associated aberrant LPA variant profile is theoretically linked to changes in hepatic LPAR expression and variant specific LPAR binding affinities. LPAR is a potential target to reduce HCC emergence. The six potent LPAR antagonists should be tested in murine models in order to determine effectiveness.

Mass Spectrometry-Based Disulfide Mapping of Lysyl Oxidase-like 2

“…The formation of aldehydes initiates crosslinking of the extracellular matrix (ECM) proteins, such as elastin and collagen leading to ECM remodeling. Significant upregulation of LOXL2 has been observed in metastatic/invasive phenotypes of tumor cells and tumors as well as fibrotic disorders [ 3 , 4 , 5 , 6 , 7 ]. Small molecule-based inhibitors of LOXL2 have been under development and some exhibited promising results from in vitro and in vivo studies [ 8 , 9 , 10 , 11 , 12 , 13 ].…”