Determinants of sensitivity to lovastatin-induced apoptosis in multiple myeloma.
Statins, commonly used to treat hypercholesterolemia, have been shown to trigger tumor-specific apoptosis in certain cancers, including multiple myeloma (MM), a plasma cell malignancy with poor prognosis. In this article, we show that of a panel of 17 genetically distinct MM cell lines, half were sensitive to statin-induced apoptosis and, despite pharmacodynamic evidence of drug uptake and activity, the remainder were insensitive. Sensitive cells were rescued from lovastatin-induced apoptosis by mevalonate, geranylgeranyl PPi, and partially by farnesyl PPi, highlighting the importance of isoprenylation. Expression profiling revealed that Rho GTPase mRNAs were differentially expressed upon lovastatin exposure in sensitive cells, yet ectopic expression of constitutively active Rho or Ras proteins was insufficient to alter sensitivity to lovastatin-induced apoptosis. This suggests that sensitivity involves more than one isoprenylated protein and that statins trigger apoptosis by blocking many signaling cascades, directly or indirectly deregulated by the oncogenic lesions of the tumor cell. Indeed, clustering on the basis of genetic abnormalities was shown to be significantly associated with sensitivity (P = 0.003). These results suggest that statins may be a useful molecular targeted therapy in the treatment of a subset of MM.
Wong
W Wei-Lynn
WW
Departments of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Clendening
James W
JW
Martirosyan
Anna
A
Boutros
Paul C
PC
Bros
Christina
C
Khosravi
Fereshteh
F
Jurisica
Igor
I
Stewart
A Keith
AK
Bergsagel
P Leif
PL
Penn
Linda Z
LZ
D017209:Apoptosis / Q000187:drug effects*; D018450:Disease Progression; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008148:Lovastatin / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000378:metabolism; D009101:Multiple Myeloma / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin; D020558:GTP Phosphohydrolases; D008798:Mevalonic Acid