Overexpression of legumain in tumors is significant for invasion/metastasis and a candidate enzymatic target for prodrug therapy.
Expression of legumain, a novel asparaginyl endopeptidase, in tumors was identified from gene expression profiling and tumor tissue array analysis. Legumain was demonstrated in membrane-associated vesicles concentrated at the invadopodia of tumor cells and on cell surfaces where it colocalized with integrins. Legumain was demonstrated to activate progelatinase A. Cells overexpressing legumain possessed increased migratory and invasive activity in vitro and adopted an invasive and metastatic phenotype in vivo, inferring significance of legumain in tumor invasion and metastasis. A prodrug strategy incorporating a legumain-cleavable peptide substrate onto doxorubicin was developed. The prototype compound, designated legubicin, exhibited reduced toxicity and was effectively tumoricidal in vivo in a murine colon carcinoma model.
Liu
Cheng
C
Departments of Immunology, The Scripps Research Institute, La Jolla, California 92037-1092, USA. chengliu@scripps.edu
Sun
Chengzao
C
Huang
Haining
H
Janda
Kim
K
Edgington
Thomas
T
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics*; D001711:Biotransformation; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D003546:Cysteine Endopeptidases / Q000096:biosynthesis* / Q000235:genetics; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism; D018093:Gelatinases / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D007930:Leucine / Q000493:pharmacokinetics; D008666:Metalloendopeptidases / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010940:Plant Proteins / Q000096:biosynthesis* / Q000235:genetics; D011355:Prodrugs / Q000493:pharmacokinetics*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D000099240:Asparaginyl Endopeptidase
D000903:Antibiotics, Antineoplastic; D003546:Cysteine Endopeptidases; D004317:Doxorubicin; D004792:Enzyme Precursors; D018093:Gelatinases; D007930:Leucine; D008666:Metalloendopeptidases; D010940:Plant Proteins; D011355:Prodrugs; D012333:RNA, Messenger; D000099240:Asparaginyl Endopeptidase; C069860:progelatinase