Regulation of melanoma metastasis to lungs by cell surface Lysosome Associated Membrane Protein-1 (LAMP1) via galectin-3.
Lysosome Associated Membrane Protein-1 (LAMP1), which lines the lysosomes, is often found to be expressed on surface of metastatic cells. We previously demonstrated that its surface expression on B16 melanoma variants correlates with metastatic potential. To establish the role of cell surface LAMP1 in metastasis and to understand the possible mechanism by which it facilitates lung colonization, LAMP1 was downregulated in high metastatic B16F10 cells using shRNAs cloned in a doxycycline inducible vector. This also resulted in significantly decreased LAMP1 on the cell surface. Being a major carrier of poly-N-acetyllactosamine (polyLacNAc) substituted β1,6 branched N-oligosaccharides, the high affinity ligands for galectin-3, LAMP1 down regulation also resulted in appreciably decreased binding of galectin-3 to the cell surface. LAMP1 has been shown to bind to Extracellular Matrix (ECM), Basement Membrane (BM) components and also to galectin-3 (via carbohydrates) which is known to get incorporated into the ECM and BM. Although, LAMP1 downregulation had a marginal effect on cellular spreading and motility on fibronectin and matrigel, it significantly altered the same on galectin-3, and ultimately leading to notably reduced lung metastasis. The results thus for the first time provide direct evidence that cell surface LAMP1 facilitates lung metastasis by providing ligands for galectin-3 which has been shown to be expressed in highest amounts on lungs and constitutively on its vascular endothelium.
Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Sector 22, Kharghar, Navi Mumbai 410210, India.
Akhil Kumar
AK
Agarwal
Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Sector 22, Kharghar, Navi Mumbai 410210, India.
Rajiv P
RP
Gude
Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Sector 22, Kharghar, Navi Mumbai 410210, India. Electronic address: rkalraiya@actrec.gov.in.
Rajiv D
RD
Kalraiya
D000818:Animals; D001485:Basement Membrane / Q000378:metabolism; D002462:Cell Membrane; D015536:Down-Regulation; D005109:Extracellular Matrix / Q000378:metabolism; D037502:Galectin 3 / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008175:Lung Neoplasms / Q000556:secondary*; D051907:Lysosomal Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008546:Melanoma, Experimental / Q000378:metabolism / Q000556:secondary*; D008810:Mice, Inbred C57BL; D034741:RNA, Small Interfering; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology*; D052118:Lysosomal-Associated Membrane Protein 1
D037502:Galectin 3; D008024:Ligands; D051907:Lysosomal Membrane Proteins; D034741:RNA, Small Interfering; C052255:Lamp1 protein, mouse; D052118:Lysosomal-Associated Membrane Protein 1
Cell surface LAMP1; Galectin-3; Lung metastasis; Motility; Poly-N-acetyllactosamine; β1,6 branched N-oligosaccharides