Abstract
BackgroundThe 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 FindingsHerein, 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/SignificanceThese 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.
Highlights
An increase rate in malignancies after organ transplantation is the toll to pay for allograft long-term survival and the posttransplant lymphoproliferation disorders (PTLD) represent the major cause of cancer-related mortality in kidney transplant recipients [1]
We previously showed that therapeutical doses of mycophenolic acid (MPA) and Ribavirin, two potent inhibitors of the inosine monophosphate dehydrogenase (IMPDH) led to the elimination of activated PBLs through a caspase-independent necrotic signal [15]
Since GTPases switch from an active, guanosine tri-phosphate (GTP)-bound, to an inactive, GDP-bound form, by the hydrolysis of GTP, we examined the effect of a GTP-locked version of Cdc42 or of Rac1 (Q61L-Rac1 was taken as control) upon MPA-mediated cell death
Summary
An increase rate in malignancies after organ transplantation is the toll to pay for allograft long-term survival and the posttransplant lymphoproliferation disorders (PTLD) represent the major cause of cancer-related mortality in kidney transplant recipients [1]. Mycophenolate mofetil (MMF) is an immunosuppressive agent widely used in transplantation the active compound of which, mycophenolic acid (MPA), depletes the intracellular pool of GTP through the inhibition of the inosine monophosphate dehydrogenase (IMPDH). Chronic myeloid leukemia (CML) is characterized by the expression of a chimeric BCR-ABL oncoprotein in hematopoietic precursor cells [6] which behaves as a potent inhibitor of apoptosis [7]. 80% to 90% of the low grade follicular nonHodgkin lymphomas resist to apoptosis through the overexpression of Bcl-2 a potent inhibitor of the mitochondriondependent apoptotic signal [9]. 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 Cdc
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