Lysyl Oxidase (LO) is the key enzyme that controls collagen and elastin maturation. LO is synthesized as a 50 kDa pro-enzyme, secreted into the extracellular environment and is then processed by proteolytic cleavage, via procollagen C-proteinases, to a functional 32 kDa enzyme and an 18 kDa pro-peptide. The LO enzyme is localized mainly extracellularly, although processed 32 kDa LO has been seen intracellularly. Importantly, LO was identified as the ras-recision gene (rrg), with ability to reduce ras-induced transformed phenotype. For example, ras-transformed NIH 3T3 cells, reverted by interferon beta/gamma, returned to their transformed phenotype upon inhibition of LO. Interestingly, ras negatively regulates LO expression. Thus, LO is down regulated in many naturally occurring and oncogene-induced tumors, and is induced concomitantly with stable phenotypic reversion, suggesting this reduction plays a role in the transformation process. Recently, we showed that LO suppresses ras-mediated activation of NF-KappaB in NIH 3T3 cells, primarily via the phosphatidylinositol-3-kinase (PI3K) pathway. Further, we have recently demonstrated that the aberrant activation of NFkappaB factors that typifies breast cancer can play a causal role in mammary tumorigenesis. Thus, here we propose to use cell culture and mouse models to test our central hypothesis that LO functions as a tumor suppressor of ras-mediated transformation via inhibiting NFkappaB activation induced by the PI3K/Akt pathway. Furthermore, we will elucidate the domains of LO mediating its ability to suppress ras-mediated transformation, and the mechanisms of oncogene-mediated reduction of LO levels. Specifically, we propose to: 1) Identify the region(s) of LO necessary for its anti-oncogenic activity in ras-transformed cells; 2) Elucidate the mechanism of LO-mediated inhibition of ras activation of PI3K; 3) Elucidate the mechanism of repression of LO gene transcription as a function of transformation; 4) Elucidate the effects of LO on mammary tumorigenesis by Ha-ras. Overall, these studies will further our understanding of the signaling mechanisms involved in the anti-oncogenic effects of LO in cancer, i.e., its ability to function as a novel tumor suppressor gene. Given that decreased expression or mutation of LO typifies many human cancers, including colon, prostate, and kidney, identification of the regulation of LO and of the domains mediating its action, may provide additional tools to modulate the amount and activity of LO and help define novel therapeutic drugs for the treatment of ras-induced cancers of multiple origins.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA082742-10
Application #
7416667
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Lei, Ming
Project Start
1999-09-01
Project End
2010-04-30
Budget Start
2008-05-01
Budget End
2010-04-30
Support Year
10
Fiscal Year
2008
Total Cost
$275,637
Indirect Cost
Name
Boston University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Bais, Manish V; Nugent, Matthew A; Stephens, Danielle N et al. (2012) Recombinant lysyl oxidase propeptide protein inhibits growth and promotes apoptosis of pre-existing murine breast cancer xenografts. PLoS One 7:e31188
Sato, Seiichi; Trackman, Philip C; Maki, Joni M et al. (2011) The Ras signaling inhibitor LOX-PP interacts with Hsp70 and c-Raf to reduce Erk activation and transformed phenotype of breast cancer cells. Mol Cell Biol 31:2683-95
Sanchez-Morgan, Nuria; Kirsch, Kathrin H; Trackman, Philip C et al. (2011) The lysyl oxidase propeptide interacts with the receptor-type protein tyrosine phosphatase kappa and inhibits *-catenin transcriptional activity in lung cancer cells. Mol Cell Biol 31:3286-97
Min, Chengyin; Zhao, Yingshe; Romagnoli, Mathilde et al. (2010) Lysyl oxidase propeptide sensitizes pancreatic and breast cancer cells to doxorubicin-induced apoptosis. J Cell Biochem 111:1160-8
Vora, Siddharth R; Guo, Ying; Stephens, Danielle N et al. (2010) Characterization of recombinant lysyl oxidase propeptide. Biochemistry 49:2962-72
Min, Chengyin; Yu, Ziyang; Kirsch, Kathrin H et al. (2009) A loss-of-function polymorphism in the propeptide domain of the LOX gene and breast cancer. Cancer Res 69:6685-93
Zhao, Yingshe; Min, Chengyin; Vora, Siddharth R et al. (2009) The lysyl oxidase pro-peptide attenuates fibronectin-mediated activation of focal adhesion kinase and p130Cas in breast cancer cells. J Biol Chem 284:1385-93
Palamakumbura, A H; Vora, S R; Nugent, M A et al. (2009) Lysyl oxidase propeptide inhibits prostate cancer cell growth by mechanisms that target FGF-2-cell binding and signaling. Oncogene 28:3390-400
Hurtado, Paola A; Vora, Siddharth; Sume, Siddika Selva et al. (2008) Lysyl oxidase propeptide inhibits smooth muscle cell signaling and proliferation. Biochem Biophys Res Commun 366:156-61
Min, Chengyin; Eddy, Sean F; Sherr, David H et al. (2008) NF-kappaB and epithelial to mesenchymal transition of cancer. J Cell Biochem 104:733-44

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