Bacteriophage hyaluronidase effectively inhibits growth, migration and invasion by disrupting hyaluronan-mediated Erk1/2 activation and RhoA expression in human breast carcinoma cells.
Aberrant hyaluronan production has been implicated in many types of tumor. In this context, hyaluronidase has been explored as a viable therapeutic approach to reduce tumoral hyaluronan. However, elevated levels of hyaluronan in tumors are often associated with high expression levels of cellular hyaluronidases, which consequently produce various sizes of saturated hyaluronan fragments with divergent pro-tumoral activities. The current study shows that different hyaluronan metabolisms of mammalian and microbial hyaluronidases could elicit distinct alterations in cancer cell behavior. Unlike saturated hyaluronan metabolites, unsaturated hyaluronan oligosaccharides produced by bacteriophage hyaluronidase, HylP, had no biological effect on growth of breast carcinoma cells. More importantly, HylP's metabolic process of hyaluronan into non-detrimental oligosaccharides significantly decreased breast cancer cell proliferation, migration and invasion by disrupting Erk1/2 activation and RhoA expression. Our results suggest that it may be possible to exploit HylP's unique enzymatic activity in suppressing hyaluronan-mediated tumor growth and progression.
Lee
Joo Hyoung
JH
Department of Physiology and Biophysics, University of Alabama, Birmingham, AL 35294-4400, USA.
Moore
Lakisha D
LD
Kumar
Sanjay
S
Pritchard
David G
DG
Ponnazhagan
Selvarangan
S
Deivanayagam
Champion
C
D000818:Animals; D001435:Bacteriophages / Q000201:enzymology; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002417:Cattle; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D006801:Humans; D006820:Hyaluronic Acid / Q000378:metabolism / Q000494:pharmacology*; D006821:Hyaluronoglucosaminidase / Q000235:genetics / Q000378:metabolism*; D015151:Immunoblotting; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009154:Mutation; D009361:Neoplasm Invasiveness; D009844:Oligosaccharides / Q000378:metabolism / Q000494:pharmacology; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
D009844:Oligosaccharides; D006820:Hyaluronic Acid; D048049:Extracellular Signal-Regulated MAP Kinases; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D006821:Hyaluronoglucosaminidase; D020742:rhoA GTP-Binding Protein