Abstract
3678
Lysyl oxidase (LOX) is an extracellular enzyme critical for the normal biosynthesis of collagens and elastin. LOX is synthesized as a 50 kDa precursor Pro-LOX and processed to a 32 kDa active enzyme and 18 kDa pro-peptide (LOX-PP). The gene encoding lysyl oxidase was identified as the ras recision gene (rrg), with the ability to revert ras-mediated transformation of NIH 3T3 fibroblasts. We have recently extended these findings to breast cancers driven by Ras and Her-2/neu, which signals via Ras (Min et al., Cancer Research, in press). In light of the high frequency of ras mutation in pancreatic (85%) and lung (25%) carcinomas, here we tested the ability of the LOX gene to repress transformation of these cancer cells. Introduction of Pro-LOX in H1299 lung cancer cells inhibited activation of Erk and Akt-dependent signaling and invasive colony formation in Matrigel. The rrg activity in these cells mapped to the LOX-PP, as we have seen previously with breast cancer cells. Ectopic LOX-PP expression in PANC-1 pancreatic cancer cells reduced activation of Erk, Akt, and NF-κB, and abrogated their ability to grow in soft agar. Thus, LOX-PP potently inhibits ras pro-oncogenic signaling and reduces invasive phenotype of lung and pancreatic cancer cells in vitro. Two single nucleotide polymorphisms (SNPs) in the pro-peptide region were reported in gastric cancers. Introduction of these SNPs resulted in a loss of the ability of LOX-PP to reverse invasive phenotype. Human breast, lung and pancreatic cancer cell lines were analyzed for these SNPs. The frequency of one of the SNPs was higher than seen in normal individuals, suggesting the polymorphisms may increase susceptibility to cancer. Thus, LOX-PP may provide a novel avenue for molecular characterization and treatment of carcinomas driven by Ras signaling.
Grant Support: This work was supported by grants from the NIH RO1 CA82742 and DOD DAMD17-05-1-0286.
98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA
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