Dysregulation of the mevalonate pathway promotes transformation

Abstract

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

Synergistic inhibitory effect of apomine and lovastatin on osteosarcoma cell growth

“…31 The recent work published by Clendening et al clearly demonstrates the key role of the mevalonate pathway in cell transformation. 32 Those authors demonstrated that ectopic overexpression of HMG-CoA reductase accentuates the growth of transformed and nontransformed cells and cooperates with Ras to drive the transformation of primary mouse embryonic fibroblast cells. Moreover, messenger RNA levels of HMG-CoA reductase were correlated with a poor prognosis in patients with breast cancer.…”

Cholesterol lowering: role in cancer prevention and treatment

“…Recent evidence suggests that statins block the adhesion and migration processes of cancer cells by disrupting membrane lipid rafts (Murai, 2012), supporting the potential therapeutic use of cholesterol lowering for suppressing various pathogenic features of cancer cells. In addition, dysregulation of the mevalonate pathway promotes transformation, suggesting that HMG-CoA reductase is a candidate metabolic oncogene, and providing further rationale for the exploration of statins as anticancer agents (Clendening et al, 2010).…”

Pravastatin induces cell cycle arrest and decreased production of VEGF and bFGF in multiple myeloma cell line

“…Wong et al (2007) showed that the sensitivity of cells to lovastatin is associated with a specific profile of genetic abnormalities. Another study (Clendening et al, 2010) attributed the sensitivity of cancer cells to statins dysregulation of the mevalonate pathway. After the evaluation of a large panel of MM cell Wong et al (2007) found that 50% of the studied strains are sensitive to lovastatin.…”