LGALS3BP, lectin galactoside-binding soluble 3 binding protein, promotes oncogenic cellular events impeded by antibody intervention

Abstract

The extracellular matrix protein lectin galactoside-binding soluble 3 binding protein (LGALS3BP) constitutes a negative prognostic marker of cancer onset and progression with increasing value in clinical application. Since its discovery, however, although the glycoprotein has been implicated in a growing number of disease-related processes, its actual role and mechanism of action have remained ambiguous, thus hindering opportunities for therapeutic development. In this study, we have determined that LGALS3BP constitutes a novel ligand for integrins α1β1, α5β1, αvβ1 and α6β1 and have identified that these newly established partnerships at the membrane level are responsible for exerting the molecule's involvement in cancer through manipulation of multiple canonical 'outside-in' integrin signalling events. We demonstrate that LGALS3BP-mediated integrin activation results into signal transmission via Akt, JNK and the Ras cascade via the Raf-ERK axis while p38 activity is kept at baseline levels. Transient cellular adherence to LGALS3BP favours survival and proliferation signalling while apoptosis is kept at bay. Sustained cellular exposure to LGALS3BP significantly supports viability, motility and migration. Importantly, an anti-LGALS3BP antibody, SP2 is capable of impeding these newly defined LGALS3BP-driven processes without, however, compromising cell viability. These novel findings reveal the mechanism of action of LGALS3BP during cellular adherence and warrant its further validation as a potential pharmacological target for anticancer therapies.

Shoc2-tranduced ERK1/2 motility signals — Novel insights from functional genomics

“…For the experimental validation we chose the LGALS3BP due to its functional connection to focal adhesion assembly and cell migration [49]. LGALS3BP was top ranked using RPKM ranking with Log 2 fold= −1.613.…”

Comparative proteome analysis across non-small cell lung cancer cell lines

“…5B). These three proteins exhibited an about fourfold higher average expression in EGFR mutants cell lines and were previously described as potential cancer targets or markers [47][48][49]. Interestingly, LGALS3BP expression correlates with distant metastasis in stage I NSCLC patients and was recently identified as a novel ligand for various integrins.…”

“…Interestingly, LGALS3BP expression correlates with distant metastasis in stage I NSCLC patients and was recently identified as a novel ligand for various integrins. In addition, it was shown to induce proliferative and anti-apoptotic signaling through integrin activation [49,50]. Thus, LGALS3BP-triggered effects may synergize with mutant EGFR signaling, which may be investigated by pharmacological interference with EGFR inhibitors and previously characterized antagonistic LGALS3BP antibody [49].…”

Lectin Galactoside-binding Soluble 3 Binding Protein (LGALS3BP) Is a Tumor-associated Immunomodulatory Ligand for CD33-related Siglecs

“…Recent studies focused more on tumor cells and transmission of signals into the tumor cell (59,60). For example, binding of LGALS3BP to integrins on tumor cells activate the Akt and Raf-Erk pathways, which was associated with increased survival, proliferation, motility, and migration of cancer cell lines (59). LGALS3BP has also been shown to induce VEGF expression in cancer cells and is associated with increased angiogenesis (60,61).…”

“…Although initial studies rapidly associated LGALS3BP with immunomodulatory effects (57,58), the exact mechanism remained unclear. Recent studies focused more on tumor cells and transmission of signals into the tumor cell (59,60). For example, binding of LGALS3BP to integrins on tumor cells activate the Akt and Raf-Erk pathways, which was associated with increased survival, proliferation, motility, and migration of cancer cell lines (59).…”