Abstract
Lysyl oxidase propeptide (LOX-PP) ectopic overexpression inhibits the growth of cancer xenografts. Here the ability and mode of action of purified recombinant LOX-PP (rLOX-PP) protein to inhibit the growth of pre-existing xenografts was determined. Experimental approaches employed were direct intratumoral injection (i.t.) of rLOX-PP protein into murine breast cancer NF639 xenografts, and application of a slow release formulation of rLOX-PP implanted adjacent to tumors in NCR nu/nu mice (n = 10). Tumors were monitored for growth, and after sacrifice were subjected to immunohistochemical and Western blot analyses for several markers of proliferation, apoptosis, and for rLOX-PP itself. Direct i.t. injection of rLOX-PP significantly reduced tumor volume on days 20, 22 and 25 and tumor weight at harvest on day 25 by 30% compared to control. Implantation of beads preloaded with 35 micrograms rLOX-PP (n = 10) in vivo reduced tumor volume and weight at sacrifice when compared to empty beads (p<0.05). A 30% reduction of tumor volume on days 22 and 25 (p<0.05) and final tumor weight on day 25 (p<0.05) were observed with a reduced tumor growth rate of 60% after implantation. rLOX-PP significantly reduced the expression of proliferation markers and Erk1/2 MAP kinase activation, while prominent increases in apoptosis markers were observed. rLOX-PP was detected by immunohistochemistry in harvested rLOX-PP tumors, but not in controls. Data provide pre-clinical findings that support proof of principle for the therapeutic anti-cancer potential of rLOX-PP protein formulations.
Highlights
Lysyl oxidase (LOX) is a copper-dependent, extracellular matrix enzyme required for the normal biosynthesis of mature and functional collagens and elastin [1]
To evaluate whether recombinant LOX-PP (rLOX-PP) protein can inhibit the growth of preexisting tumors in vivo, we used a breast cancer xenograft model
The data show that i.t. injection of rLOX-PP significantly inhibits the tumor volume growth by 28% on day 25 and growth rate by 32% after day 18 compared to PBS, and a trend toward diminished tumor weight was found
Summary
Lysyl oxidase (LOX) is a copper-dependent, extracellular matrix enzyme required for the normal biosynthesis of mature and functional collagens and elastin [1]. LOX is made as a 50 kDa proenzyme and processed extracellularly to a ,30 kDa mature LOX enzyme and the ,18 kDa propeptide (LOX-PP) by procollagen C-proteinases [2], encoded by the bone morphogenetic protein-1 and the tolloid-like-1 and -2 genes [3,4]. The LOX gene has been shown to have ‘‘RAS rescission’’ activity, and this tumor suppressor activity of the LOX gene has been mapped to its propeptide region [5]. LOX enzyme activity has been reported to promote tumor invasiveness [7,8]. Estrogen receptor positive breast cancer tumors are less invasive than estrogen receptor negative tumors, and express lower levels of LOX mRNA [9]. Data suggest a model in which abnormally low levels of LOX-PP may permit tumor growth, whereas abnormally high LOX enzyme may promote tumor invasion. Our interest here is to investigate the potential of rLOXPP protein to inhibit tumor growth in vivo
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