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Prepublished online as a Blood First Edition Paper on February 27, 2003; DOI 10.1182/blood-2002-08-2547.
Submitted August 19, 2002
Accepted February 5, 2003
Induction of apoptosis in IL-3-dependent hematopoietic cell lines by guanine nucleotide depletion
Jing J Gu, Karen Gathy, Lalaine Santiago, Eric Chen, Min Huang, Lee M Graves, and Beverly S Mitchell*
Departments of Pharmacology and Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
* Corresponding author; email: mitchell{at}med.unc.edu.
Inosine 5'-monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme that catalyzes the conversion of IMP to XMP at the branch point of purine nucleotide biosynthesis, leading to the generation of guanine nucleotides. Inhibition of IMPDH results in depletion of guanine nucleotides, prevents cell growth by G1 arrest, and induces cell differentiation in a cell type-specific manner. The molecular and sensing mechanisms underlying these effects are not clear. We have examined the induction of apoptosis by mycophenolic acid (MPA), a specific IMPDH inhibitor, in interleukin-3 dependent murine hematopoietic cell lines. MPA treatment, at clinically relevant doses, caused apoptosis in 32D myeloid cells and in FL5.12 and BaF3 pre-B cells in the ongoing presence of IL-3. Apoptosis was completely prevented by the addition of guanosine at time points up to 12 hours, after which time caspase 3 activity increased and apoptosis was not reversible. MPA treatment caused marked downregulation of the MEK/Erk pathway at 3h, while simultaneously increasing the phosphorylation of c-Jun kinase. In addition, MPA strongly downregulated the mTOR (mammalian target of rapamcyin) pathway as indicated by decreased phosphorylation of p70 S6 kinase and of 4EBP1. Inhibition of either the MAP kinase or the mTOR pathway alone by standard pharmacological inhibitors did not induce apoptosis in IL-3 dependent cells, whereas inhibition of both pathways simulated the effects of MPA treatment. These results indicate that IMPDH inhibitors may be effective in modulating signal transduction pathways in hematopoietic cells, suggesting their utility in chemotherapeutic regimens for hematological malignancies.
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