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- Title
A critical role for Akt in macrophage cytotoxicity to antibody-coated tumor cells.
- Authors
Joshi, Trupti; Ganesan, Latha P.; Cheney, Carolyn; Muthusamy, Natarajan; Byrd, John C.; Ostrowski, Michael C.; Tridandapani, Susheela
- Abstract
Objective: To examine the signaling pathways critical for macrophage cytotoxicity to antibody-coated tumor targets. Methods: Using a human B cell lymphoma cell line coated with Rituximab as a tumor model the cytotoxic ability of murine macrophages was measured by 51Cr-release assays. In addition, biochemical, pharmacological and genetic approaches were used to identify molecular mechanisms of macrophage cytotoxicity. Findings: We first demonstrate that interaction of macrophages with antibody-coated tumor targets leads to the activation of multiple signaling events including the activation of tyrosine kinases and PI3K. Inhibition of PI3K activation completely abolished cytotoxicity indicating that the PI3K/Akt pathway is necessary for macrophage ADCC. Consistent with this, murine peritoneal macrophages expressing overactive Akt showed significantly enhanced ADCC. Further, studies showed that in this model of macrophage ADCC, cytotoxicity is dependent upon release of nitric oxide (NO). We hypothesize that Akt enhances macrophage cytotoxicity by promoting. NO production. We are currently testing this hypothesis. Conclusion: Together these findings illustrate a novel role for Akt in the clearance of antibody-coated tumor cells, and suggest that manipulation of Akt may enhance the efficacy of monoclonal antibody therapy for cancer.
- Subjects
PROTEIN kinases; CELL-mediated cytotoxicity; MACROPHAGES; CELLS; PROTEINS
- Publication
FASEB Journal, 2007, Vol 21, Issue 5, pA184
- ISSN
0892-6638
- Publication type
Article