The Necrotic Signal Induced by Mycophenolic Acid Overcomes Apoptosis-Resistance in Tumor CellsReport as inadecuate




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Background

The amount of inosine monophosphate dehydrogenase IMPDH, a pivotal enzyme for the biosynthesis of the guanosine tri-phosphate GTP, is frequently increased in tumor cells. The anti-viral agent ribavirin and the immunosuppressant mycophenolic acid MPA are potent inhibitors of IMPDH. We recently showed that IMPDH inhibition led to a necrotic signal requiring the activation of Cdc42.

Methodology-Principal Findings

Herein, we strengthened the essential role played by this small GTPase in the necrotic signal by silencing Cdc42 and by the ectopic expression of a constitutive active mutant of Cdc42. Since resistance to apoptosis is an essential step for the tumorigenesis process, we next examined the effect of the MPA–mediated necrotic signal on different tumor cells demonstrating various mechanisms of resistance to apoptosis Bcl2-, HSP70-, Lyn-, BCR-ABL–overexpressing cells. All tested cells remained sensitive to MPA–mediated necrotic signal. Furthermore, inhibition of IMPDH activity in Chronic Lymphocytic Leukemia cells was significantly more efficient at eliminating malignant cells than apoptotic inducers.

Conclusions-Significance

These findings indicate that necrosis and apoptosis are split signals that share few if any common hub of signaling. In addition, the necrotic signaling pathway induced by depletion of the cellular amount of GTP-GDP would be of great interest to eliminate apoptotic-resistant tumor cells.



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Source: http://plos.srce.hr/



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