ausblenden:
Schlagwörter:
TUMOR-ASSOCIATED ANTIGEN, HUMAN HEPATOMA-CELLS, EXTRACELLULAR-MATRIX,
MAC-2-BINDING PROTEIN, PROSTATE-CANCER, GASTRIC-CANCER, LUNG-CARCINOMA,
BREAST-CANCER, 90K, ACTIVATIONOncology; LGALS3BP, cancer biomarker, extracellular matrix, integrin signalling,
therapeutic target;
Zusammenfassung:
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
alpha(1)beta(1), alpha(5)beta(1), alpha(v)beta(1) and alpha(6)beta(1)
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.
