Cell surface interaction of annexin A2 and galectin-3 modulates epidermal growth factor receptor signaling in Her-2 negative breast cancer cells
Overexpression and activation of tyrosine kinase receptors like EGFR and Src regulate the progression and metastasis of Her-2 negative breast cancer. Recently we have reported the role of cell membrane interaction of phospholipid-binding protein annexin A2 (AnxA2) and EGFR in regulating cellular signaling in the activation of angiogenesis, matrix degradation, invasion, and cancer metastasis. Beta-galactoside-specific animal lectin galectin-3 is an apoptosis inhibitor, and cell surface-associated extracellular galectin-3 also has a role in cell migration, cancer progression, and metastasis. Similar expression pattern and membrane co-localization of these two proteins made us to hypothesize in the current study that galectin-3 and AnxA2 interaction is critical for Her-2 negative breast cancer progression. By various experimental analyses, we confirm that glycosylated AnxA2 at the membrane surface interacts with galectin-3. N-linked glycosylation inhibitor tunicamycin treatment convincingly blocked AnxA2 membrane translocation and its association with galectin-3. To analyze whether this interaction has any functional relevance, we tried to dissociate this interaction with purified plant lectin from chickpea (Cicer arietinum agglutinin). This highly specific 30 kDa plant lectin could dissociate AnxA2 from endogenous lectin galectin-3 interaction at the cell surface. This dissociation could down-regulate Bcl-2 family proteins, cell proliferation, and migration simultaneously triggering cell apoptosis. Targeting this interaction of membrane surface glycoprotein and its animal lectin in Her-2 negative breast cancer may be of therapeutic value.
KeywordsAnxA2 Galectin-3 EGFR Animal lectin Her-2 Breast cancer
Triple-negative breast cancer
Epidermal growth factor receptor
Epidermal growth factor receptor-2, ERbB-2
Signal transducer and activator of transcription
Extracellular signal-regulated kinases
Receptor tyrosine kinase
Glyceraldehyde-3 phosphate dehydrogenase
Polyacrylamide gel electrophoresis
Fetal bovine serum
Methyl thiazol tetrazolium
Tissue-type plasminogen activator
Authors like to acknowledge Mr. Harikrishna Ellanki for technical help.
Compliance with ethical standards
Conflicts of interests
The authors have declared that no competing interests exist.
This work was supported by Indian Council of Medical Research (ICMR) Ad hoc grant, IRIS No. 09390 to Dr. Praveenkumar Shetty, partly by SDM Institutional grant and seed funding from Karnataka Cancer Therapy and Research Institute, Hubli. The funders had no role in study design, data collection, and analysis, decision to publish or preparation of the manuscript.
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