Abstract

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.