Protein geranylgeranylation is critical for the regulation of survival and proliferation of lymphoma tumor cells.
OBJECTIVE
Prenylation is essential for membrane localization and participation of proteins in various signaling pathways. The following study was conducted to examine the importance of protein farnesylation and geranylgeranylation for the regulation of lymphoma cell survival and proliferation.


METHODS
Lymphoma cells were treated with the beta-hydroxy-beta-methylglutaryl-CoA reductase inhibitor lovastatin, which inhibits protein farnesylation and geranylgeranylation by the depletion of intracellular pools of farnesylpyrophosphate and geranylgeranylpyrophosphate. In addition, farnesyl transferase and geranylgeranyl transferase activities were specifically inhibited by FTI-277 and GGTI-298, respectively.


RESULTS
Only inhibition of geranylgeranylation by lovastatin led to reduction of cell viability in lymphoma cell lines and purified tumor cells from lymphoma patients in a time- and dose-dependent way. Reduction in the number of viable cells was mediated by both induction of apoptosis and inhibition of proliferation. In addition, GGTI-298 was more effective in induction of apoptosis and inhibition of proliferation than FTI-277. Apoptosis induced by inhibition of protein geranylgeranylation was associated with a reduction of Mcl-1 protein levels, collapse of the mitochondrial transmembrane potential, and caspase-3 activation. Inhibition of proliferation resulted from the induction of G(1) arrest. Furthermore, lovastatin at low concentrations sensitized lymphoma cells to dexamethasone, including cells resistant to this drug.


CONCLUSIONS
These results indicate that protein geranylgeranylation is critical for the regulation of lymphoma tumor cell survival and proliferation and that pharmacological agents such as lovastatin or geranylgeranyl transferase inhibitors, alone or in combination with other drugs, may be useful in the treatment of lymphoma.
van de Donk
Niels W C J
NW
Department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
Schotte
Diana
D
Kamphuis
Marloes M J
MM
van Marion
Ariënne M W
AM
van Kessel
Berris
B
Bloem
Andries C
AC
Lokhorst
Henk M
HM
D000328:Adult; D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology*; D004224:Diterpenes / Q000378:metabolism*; D005260:Female; D006801:Humans; D008148:Lovastatin / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D019821:Simvastatin / Q000494:pharmacology
D000806:Angiotensin-Converting Enzyme Inhibitors; D004224:Diterpenes; C040155:geranylgeranic acid; D008148:Lovastatin; D019821:Simvastatin