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SCH 51344, an inhibitor of RAS/RAC-mediated cell morphology pathway
C C Kumar1, K Ohashi, K Nagata
1Department of Tumor Biology, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA. Chandra.kumar@spcorp.com
Abstract:
RAS interacts with multiple targets in the cell and controls at least two signaling pathways, one regulating extracellular signal-regulated kinase (ERK) activation and the other controlling membrane ruffling formation. These two pathways appear to act synergistically to cause transformation. Human smooth muscle alpha-actin promoter is repressed in RAS-transformed cells and derepressed in revertant cell lines, suggesting that it is a sensitive marker to follow phenotypic changes in fibroblast cells. SCH 51344 is a pyrazoloquinoline derivative identified on the basis of its ability to derepress alpha-actin promoter in RAS-transformed cells. Previous studies have shown that SCH 51344 is a potent inhibitor of RAS transformation. However, SCH 51344 had very little effect on the activities of proteins in the ERK pathway, suggesting that it inhibits RAS transformation by a novel mechanism. Recently, we have demonstrated that SCH 51344 specifically blocks membrane ruffling induced by activated forms of H-RAS, K-RAS, N-RAS, and RAC. Treatment of fibroblast cells with this compound had very little effect on RAS-mediated activation of ERK and JUN kinase activities. SCH 51344 was effective in inhibiting the anchorage-independent growth of Rat-2 fibroblast cells transformed by the three forms of oncogenic RAS and RAC V12. These results indicate that SCH 51344 inhibits a critical component of the membrane ruffling pathway downstream from RAC and suggest that targeting this pathway may be an effective approach to inhibiting transformation by RAS and other oncogenes.
Insights
SCH 51344 inhibits RAS transformation by blocking membrane ruffling, a key pathway distinct from ERK signaling. This compound offers a novel mechanism for targeting oncogene-induced cell transformation.
Area of Science:
- Cell Biology
- Molecular Oncology
- Signal Transduction
Background:
- RAS proteins are key regulators of cell signaling pathways, including ERK activation and membrane ruffling, which synergistically drive cell transformation.
- The human smooth muscle alpha-actin promoter serves as a sensitive marker for phenotypic changes in RAS-transformed fibroblasts.
- SCH 51344, a pyrazoloquinoline derivative, was identified for its ability to derepress the alpha-actin promoter in RAS-transformed cells.
Purpose of the Study:
- To investigate the mechanism of action of SCH 51344, a potent inhibitor of RAS transformation.
- To determine if SCH 51344 targets the ERK pathway or another mechanism in RAS-mediated transformation.
- To evaluate SCH 51344's efficacy in inhibiting anchorage-independent growth of oncogene-transformed cells.
Main Methods:
- Assessing the effect of SCH 51344 on ERK and JUN kinase activities in RAS-transformed cells.
- Analyzing SCH 51344's impact on membrane ruffling induced by activated RAS and RAC.
- Evaluating SCH 51344's inhibition of anchorage-independent growth in Rat-2 fibroblast cells transformed by oncogenic RAS and RAC V12.
Main Results:
- SCH 51344 demonstrated minimal impact on ERK and JUN kinase pathway activities.
- SCH 51344 specifically inhibited membrane ruffling induced by activated H-RAS, K-RAS, N-RAS, and RAC.
- SCH 51344 effectively inhibited the anchorage-independent growth of fibroblast cells transformed by oncogenic RAS and RAC V12.
Conclusions:
- SCH 51344 inhibits RAS transformation through a novel mechanism targeting the membrane ruffling pathway, downstream of RAC.
- The membrane ruffling pathway represents a critical component in RAS-mediated cell transformation.
- Targeting the membrane ruffling pathway offers a promising therapeutic strategy for inhibiting transformation driven by RAS and other oncogenes.