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Molecular Cancer Research 1:701-706 (2003)
© 2003 American Association for Cancer Research

Angiogenesis, Metastasis, and the Cellular Microenvironment

Tetrathiomolybdate Inhibits Angiogenesis and Metastasis Through Suppression of the NF{kappa}B Signaling Cascade1

Quintin Pan1, Li Wei Bao1 and Sofia D. Merajver1

Department of Internal Medicine, Division of Hematology and Oncology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI

Requests for reprints: Sofia D. Merajver, Department of Internal Medicine, Division of Hematology and Oncology and Comprehensive Cancer Center, University of Michigan Medical School, 1500 East Medical Center Drive, Ann Arbor, MI 48109. E-mail: smerajve{at}umich.edu

Tetrathiomolybdate (TM), a specific copper chelator, has been shown to be a potent antiangiogenic and antimetastatic compound possibly through suppression of the NF{kappa}B signaling cascade. To further delineate the molecular mechanism of the anticancer effect of TM, we investigated whether TM has antineoplastic activity in the setting of genetic NF{kappa}B inhibition. In this study, SUM149 inflammatory breast carcinoma cells were transfected with a dominant-negative I{kappa}B{alpha} (S32AS36A) expression vector. Similar to TM-treated SUM149 cells, SUM149-I{kappa}B{alpha}Mut clones secreted lower amounts of proangiogenic mediators, vascular endothelial growth factor, interleukin-1{alpha}, and interleukin-8 and exhibited a less invasive and motile phenotype. The reduction in the angiogenic and metastatic potential of SUM149-I{kappa}B{alpha}Mut clones was not further affected by TM in vitro. SUM149-I{kappa}B{alpha}Mut xenografts grew substantially slower and had less lung metastasis than SUM149 and SUM149-empty vector xenografts. The growth and metastatic potential of SUM149 and SUM149-empty tumors was significantly inhibited with systemic TM treatment, whereas TM had no further antitumor effect on the SUM149-I{kappa}B{alpha}Mut tumors. Additionally, nuclear proteins isolated from TM-treated SUM149 tumors had lower NF{kappa}B binding activity, while AP1 and SP1 binding activities were unchanged. Taken together, these results strongly support that suppression of NF{kappa}B is the major mechanism used by TM to inhibit angiogenesis and metastasis.

Key Words: angiogenesis • copper • carcinoma




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