Bacteriophage hyaluronidase effectively inhibits growth, migration and invasion by disrupting hyaluronan-mediated Erk1/2 activation and RhoA expression in human breast carcinoma cells

Lee, Joo Hyoung; Moore, Lakisha D.; Kumar, Sanjay; Pritchard, David G.; Ponnazhagan, Selvarangan; Deivanayagam, Champion

doi:10.1016/j.canlet.2010.07.011

« Previous Next »Cancer Letters
Volume 298, Issue 2 , Pages 238-249, 8 December 2010

Bacteriophage hyaluronidase effectively inhibits growth, migration and invasion by disrupting hyaluronan-mediated Erk1/2 activation and RhoA expression in human breast carcinoma cells

Joo Hyoung Lee
- Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, AL 35294-4400, United States
- Center for Biophysical Sciences and Engineering, University of Alabama at Birmingham, Birmingham, AL 35294-4400, United States
Lakisha D. Moore
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294-4400, United States
Sanjay Kumar
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294-4400, United States
David G. Pritchard
- Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294-4400, United States
Selvarangan Ponnazhagan
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294-4400, United States
Champion Deivanayagam
- Department of Vision Sciences, University of Alabama at Birmingham, Birmingham, AL 35294-4400, United States
- Center for Biophysical Sciences and Engineering, University of Alabama at Birmingham, Birmingham, AL 35294-4400, United States
- Corresponding author. Address: Department of Vision Sciences, Center for Biophysical Sciences and Engineering, University of Alabama at Birmingham, 1025 18th Street South, CBSE 100, Birmingham, AL 35294-4400, United States. Tel.: +1 205 934 6026; fax: +1 205 934 0480.

Received 7 April 2010; received in revised form 8 July 2010; accepted 12 July 2010. published online 05 August 2010.

Abstract

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.

Keywords: Hyaluronan, Hyaluronidase, BTH, HylP, Breast carcinoma