Taxol and LPS Modulation of c-kit and nm23 Expression in Macrophages and Normal vs. Malignant Breast Cancer Cell Lines

摘要

Apart from its well characterized anti-mitotic effects, Taxol shares with bacterial lipopolysaccharide (LPS) the capacity to elicit microtubule-independent, intracellular signaling in murine macrophages leading to expression of many genes. This IDEA grant proposed to test the ability of Taxol to up-regulate expression of two genes, nm23 and c-kit, whose expression is down-regulated in advanced, metatstatic breast cancer. Modulation of adrenomedulin (AM), as well as a panel of inflammatory genes, were also examined in murine macrophages and/or breast cancer cells stimulated by LPS or Taxol. Using optimized conditions for detection of mRNA species by reverse transcriptase polymerase chain reaction (RT-PCR): (1) we completed studies on the modulation of AM in macrophages, (2) demonstrated differential modulation of NM-23 and c-kit mRNA in the murine breast cancer cell line, DA-3, and (3) demonstrated that LPS and/or Taxol strongly up-regulate expression of a panel pro-inflammatory genes in a murine (DA-3) and a human (MDA-MB-231) breast cancer cell lines. (4) Lastly, in the presence of DA-3 tumor cells, stimulation of macrophages by LPS or Taxol plus IPN-gamma results is a significant increase in the capacity of the macrophages to release nitric oxide (NO), shown previously to be tumoricidal.