期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 107, 期 34, 页码 15051-15056出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0910258107
关键词
HMGCR; hydroxymethylglutaryl coenzyme A reductase; cancer; metabolic oncogene; tumor metabolism
资金
- Canada Research Chairs Program
- Ontario Institute for Cancer Research through Province of Ontario
- Canadian Breast Cancer Foundation
- Canadian Institutes for Health Research
- Leukemia and Lymphoma Society of Canada
- Ontario Graduate Scholarship
- Natural Sciences and Engineering Research Council
- Canada Foundation for Innovation
- IBM
- CIHR
The importance of cancer metabolism has been appreciated for many years, but the intricacies of how metabolic pathways inter-connect 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.
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