The importance of cancer metabolism has been appreciated for many years, but the intricacies of how metabolic pathways interconnect with oncogenic signaling are not fully understood. With a clear understanding of how metabolism contributes to tumorigenesis, we will be better able to integrate the targeting of these fundamental biochemical pathways into patient care. The mevalonate (MVA) pathway, paced by its rate-limiting enzyme, hydroxymethylglutaryl coenzyme A reductase (HMGCR), is required for the generation of several fundamental end-products including cholesterol and isoprenoids. Despite years of extensive research from the perspective of cardiovascular disease, the contribution of a dysregulated MVA pathway to human cancer remains largely unexplored. We address this issue directly by showing that dysregulation of the MVA pathway, achieved by ectopic expression of either full-length HMGCR or its novel splice variant, promotes transformation. Ectopic HMGCR accentuates growth of transformed and nontransformed cells under anchorage-independent conditions or as xenografts in immunocompromised mice and, importantly, cooperates with RAS to drive the transformation of primary mouse embryonic fibroblasts cells. We further explore whether the MVA pathway may play a role in the etiology of human cancers and show that high mRNA levels of HMGCR and additional MVA pathway genes correlate with poor prognosis in a meta-analysis of six microarray datasets of primary breast cancer. Taken together, our results suggest that HMGCR is a candidate metabolic oncogene and provide a molecular rationale for further exploring the statin family of HMGCR inhibitors as anticancer agents.HMGCR | hydroxymethylglutaryl coenzyme A reductase | cancer | metabolic oncogene | tumor metabolism

The mevalonate pathway is a core biochemical process, crucial for the generation of cholesterol and other key metabolic end products. The rate-limiting enzyme of the mevalonate pathway, hydroxymethylglutaryl coenzyme A reductase (HMGCR), is safely and effectively targeted by the statin family of inhibitors to treat hypercholesterolemia. The anticancer activity of statins has also been widely reported, yet the tumor-selective mechanisms that mediate these antiproliferative effects remain largely unclear. The importance of altered metabolism in the context of tumorigenesis has received renewed attention as metabolic changes entwined with the molecular hallmarks of cancer have been elucidated. Although several metabolic pathways have been linked to cancer progression and etiology, it was only recently that HMGCR and the mevalonate pathway were also shown to have a distinct role in cellular transformation. In this review, we chart the historical progression of statins from cholesterol-lowering blockbusters to anticancer agents with imminent potential, and further discuss an emerging role for HMGCR and the mevalonate pathway in the metabolic reprogramming of cancer.

BackgroundOvarian carcinoma is a rarely curable disease, for which new treatment options are required. As agents that block HMG-CoA reductase and the mevalonate pathway, the statin family of drugs are used in the treatment of hypercholesterolemia and have been shown to trigger apoptosis in a tumor-specific manner. Recent clinical trials show that the addition of statins to traditional chemotherapeutic strategies can increase efficacy of targeting statin-sensitive tumors. Our goal was to assess statin-induced apoptosis of ovarian cancer cells, either alone or in combination with chemotherapeutics, and then determine these mechanisms of action.MethodsThe effect of lovastatin on ovarian cancer cell lines was evaluated alone and in combination with cisplatin and doxorubicin using several assays (MTT, TUNEL, fixed PI, PARP cleavage) and synergy determined by evaluating the combination index. The mechanisms of action were evaluated using functional, molecular, and pharmacologic approaches.ResultsWe demonstrate that lovastatin induces apoptosis of ovarian cancer cells in a p53-independent manner and synergizes with doxorubicin, a chemotherapeutic agent used to treat recurrent cases of ovarian cancer. Lovastatin drives ovarian tumor cell death by two mechanisms: first, by blocking HMG-CoA reductase activity, and second, by sensitizing multi-drug resistant cells to doxorubicin by a novel mevalonate-independent mechanism. This inhibition of drug transport, likely through inhibition of P-glycoprotein, potentiates both DNA damage and tumor cell apoptosis.ConclusionsThe results of this research provide pre-clinical data to warrant further evaluation of statins as potential anti-cancer agents to treat ovarian carcinoma. Many statins are inexpensive, off-patent generic drugs that are immediately available for use as anti-cancer agents. We provide evidence that lovastatin triggers apoptosis of ovarian cancer cells as a single agent by a mevalonate-dependent mechanism. Moreover, we also show lovastatin synergizes with doxorubicin, an agent administered for recurrent disease. This synergy occurs by a novel mevalonate-independent mechanism that antagonizes drug resistance, likely by inhibiting P-glycoprotein. These data raise important issues that may impact how statins can best be included in chemotherapy regimens.

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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. [Mol Cancer Ther 2007;6(6):1886 -97]

Statins, routinely used to treat hypercholesterolemia, selectively induce apoptosis in some tumor cells by inhibiting the mevalonate pathway. Recent clinical studies suggest that a subset of breast tumors is particularly susceptible to lipophilic statins, such as fluvastatin. To quickly advance statins as effective anticancer agents for breast cancer treatment, it is critical to identify the molecular features defining this sensitive subset. We have therefore characterized fluvastatin sensitivity by MTT assay in a panel of 19 breast cell lines that reflect the molecular diversity of breast cancer, and have evaluated the association of sensitivity with several clinicopathological and molecular features. A wide range of fluvastatin sensitivity was observed across breast tumor cell lines, with fluvastatin triggering cell death in a subset of sensitive cell lines. Fluvastatin sensitivity was associated with an estrogen receptor alpha (ERα)-negative, basal-like tumor subtype, features that can be scored with routine and/or strong preclinical diagnostics. To ascertain additional candidate sensitivity-associated molecular features, we mined publicly available gene expression datasets, identifying genes encoding regulators of mevalonate production, non-sterol lipid homeostasis, and global cellular metabolism, including the oncogene MYC. Further exploration of this data allowed us to generate a 10-gene mRNA abundance signature predictive of fluvastatin sensitivity, which showed preliminary validation in an independent set of breast tumor cell lines. Here, we have therefore identified several candidate predictors of sensitivity to fluvastatin treatment in breast cancer, which warrant further preclinical and clinical evaluation.

Using an expression cloning approach, we identify CUL7, a member of the cullin family, as a functional inhibitor of Mycinduced apoptosis. Deregulated expression of the Myc oncogene drives cellular proliferation yet also sensitizes cells to undergo p53-dependent and p53-independent apoptosis. Here, we report that CUL7 exerts its antiapoptotic function through p53. CUL7 binds directly to p53, and small interfering RNA-mediated knockdown of CUL7 results in the elevation of p53 protein levels. This antiapoptotic role of CUL7 enables this novel oncogene to cooperate with Myc to drive transformation. Deregulated ectopic expression of c-Myc and CUL7 promotes Rat1a cell growth in soft agar, and knockdown of CUL7 significantly blocks human neuroblastoma SHEP cell growth in an anchorage-independent manner. Furthermore, using public microarray data sets, we show that CUL7 mRNA is significantly overexpressed in non-small cell lung carcinoma and is associated with poor patient prognosis. We provide experimental evidence to show CUL7 is a new oncogene that cooperates with Myc in transformation by blocking Mycinduced apoptosis in a p53-dependent manner. [Cancer Res 2007;67(20):9616-22]

Statins, prescribed for decades to control cholesterol, have more recently been shown to have promising anticancer activity. Statins induce tumor-selective apoptosis by inhibiting the mevalonate (MVA) pathway. In addition, we have recently demonstrated that lovastatin modulates drug accumulation in a MVA-independent manner in multidrug-resistant (MDR) tumor cells overexpressing the P-glycoprotein (P-gp) multidrug transporter. P-gp-mediated drug efflux can contribute to chemotherapy failure. However, direct statin-mediated inhibition of P-gp in human MDR tumor cells at clinically achievable concentrations remains unexplored. An understanding of these interactions is crucial, both to appreciate differences in the anticancer potential of different statins and to safely and effectively integrate statins into traditional chemotherapy regimens that include P-gp substrates. Here we evaluate interactions between 4 statins (lovastatin, atorvastatin, fluvastatin and rosuvastatin) and P-gp, at both the molecular level using purified P-gp and at the cellular level using human MDR tumor cells. Lovastatin bound directly to purified P-gp with high affinity and increased doxorubicin accumulation in MDR tumor cells, potentiating DNA damage, growth arrest and apoptosis. By contrast, while atorvastatin inhibited substrate transport by purified P-gp in proteoliposomes, it had no effect on doxorubicin transport in MDR tumor cells. Finally, fluvastatin and rosuvastatin only interacted with P-gp in vitro at high concentrations and did not inhibit doxorubicin transport in MDR cells. These differential interactions should be considered when combining statins with traditional chemotherapeutic drugs.