Lysyl oxidase-like 2 (LOXL2) belongs to the lysyl oxidase (LOX) family. As an extracellular enzyme, LOXL2 participates in the maturation and remodeling of the extracellular matrix (ECM) by catalyzing the cross-linking of collagen and elastin fibers. This function is associated with various physiological and pathological processes, such as fibrosis and cardiovascular disease .
(Data source: Poe A, et al. Am J Physiol Cell Physiol. 2023)
LOXL2 expression distribution
Normal tissues: expressed at low levels in the placenta, lungs, heart, skin, etc., and participates in physiological development and wound healing.
Tumor tissue: It is significantly upregulated in various solid tumors such as gastric cancer, breast cancer, liver cancer, pancreatic cancer, cervical cancer, head and neck squamous cell carcinoma, and prostate cancer, and is associated with lymph node metastasis and poor prognosis.
(Data source: Uniprot)
Structure of LOXL2
LOXL2 is a secreted protein that consists of an N-terminal signal peptide (essential for secretion); four scavenger receptor cysteine-rich (SRCR) domains (mediating protein-protein/matrix interactions); a catalytic domain containing a Cu²⁺ binding site and a lysyltyrosine quinone (LTQ) cofactor, responsible for amine oxidase activity; and a C-terminal non-catalytic domain involved in zymogen activation and nuclear localization.
(Data source: Asthana S. Liverpool Int Commun. 2024)
LOXL2 targets in tumors
Targets of Secreted LOXL2: LOXL2 triggers ECM remodeling and activates the FAK signaling pathway in fibroblasts and tumor cells. Additionally, it stimulates the AKT and ERK signaling pathways in tumor cells. LOXL2 oxidizes PDGFRβ, enhances ERK signaling in fibroblasts, and increases the secretion of lymphangiogenic factors (VEGFC and SDF-1α).
Intracellular targets of LOXL2: LOXL2 can influence diverse cellular processes by interacting with various effectors located either at the plasma membrane (i.e., ERBB2 receptor and ITGA5/ITGB1 integrin) or in the cytoplasm (FAK, ezrin, VIM, AKT, MARKSL1, ERK1/2, IQGAP1, and ALDOA), impacting diverse tumor environments. Interaction between LOXL2 and HSPA5/BiP in the endoplasmic reticulum leads to activation of the transcription factor XBP1, which in turn upregulates multiple EMT-TFs.
Nuclear targets of LOXL2: In different tumor scenarios, nuclear LOXL2 exerts its pro-tumor effects by interacting with various transcription factors (SNAI1, E47, KLF4, and GATA6), modifying histone marks (H3K4me3 and H3K36ac), and upregulating the expression of different effectors (HIF1, SMO/GLI, and RAMP3).
(Data source: Cano A. Int J Mol Sci. 2023)
LOXL2-targeted therapy
Strategies for blocking the effects of LOXL2 on tumor progression include the generation of anti-LOXL2 antibodies and small molecule inhibitors, with the ultimate goal of interfering with the tumor-promoting effects of LOXL2.
Simtuzumab, a humanized antibody targeting the SRCR4 domain of LOXL2, was developed by Gilead Sciences and was used in several randomized Phase II clinical trials targeting different pathologies. However, in none of these trials did the antibody improve clinical outcomes. On January 5, 2016, Gilead Sciences announced that it had discontinued its Phase II clinical study in patients with idiopathic pulmonary fibrosis.
(Data source: Cano A. Int J Mol Sci. 2023)
