Premium
A critical role for Akt in macrophage cytotoxicity to antibody‐coated tumor cells
Author(s) -
Joshi Trupti,
Ganesan Latha P.,
Cheney Carolyn,
Muthusamy Natarajan,
Byrd John C.,
Ostrowski Michael C.,
Tridandapani Susheela
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a184-a
Subject(s) - antibody dependent cell mediated cytotoxicity , cytotoxicity , protein kinase b , macrophage , pi3k/akt/mtor pathway , cancer research , monoclonal antibody , chemistry , cytotoxic t cell , antibody , immunology , biology , microbiology and biotechnology , signal transduction , biochemistry , in vitro
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 51 Cr‐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. Support by NIH: P01 CA095426 ; R01 AI059406