Statins and Cancer Risk

Karp, Igor; Behlouli, Hassan; LeLorier, Jacques; Pilote, Louise

doi:10.1016/j.amjmed.2007.12.011

Cited by 120 publications

(79 citation statements)

References 34 publications

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“…Exogenous MVA administered to xenograft-bearing mice was also shown to promote tumor growth (14). Finally, recent epidemiological studies have shown that patients taking certain statins for cholesterol control displayed a decreased risk of developing some cancers (15)(16)(17)(18)(19)(20)(21). Taken together, these results suggest that HMGCR may play an important role in human malignancies.…”

supporting

confidence: 53%

Dysregulation of the mevalonate pathway promotes transformation

Clendening

Pandyra

Boutros

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

346

306

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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

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supporting

confidence: 53%

Dysregulation of the mevalonate pathway promotes transformation

Clendening

Pandyra

Boutros

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

346

306

View full text Add to dashboard Cite

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“…Especially for bladder cancer, the results are conflicting [37][38][39]. Another complication is a substantial interindividual heterogeneity in therapeutic response to statins [20].…”

Section: Discussionmentioning

confidence: 98%

Establishment and characterization of a bladder cancer cell line with enhanced doxorubicin resistance by mevalonate pathway activation

et al. 2015

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Resistance to chemotherapy is a major problem in the treatment of urothelial bladder cancer. Several mechanisms have been identified in resistance to doxorubicin by analysis of resistant urothelial carcinoma (UC) cell lines, prominently activation of drug efflux pumps and diminished apoptosis. We have derived a new doxorubicin-resistant cell line from BFTC-905 UC cells, designated BFTC-905-DOXO-II. A doxorubicin-responsive green fluorescent protein (GFP) reporter assay indicated that resistance in BFTC-905-DOXO-II was not due to increased drug efflux pump activity, whereas caspase-3/7 activation was indeed diminished. Gene expression microarray analysis revealed changes in proapoptotic and antiapoptotic genes, but additionally induction of the mevalonate (cholesterol) biosynthetic pathway. Treatment with simvastatin restored sensitivity of BFTC-905-DOXO-II to doxorubicin to that of the parental cell line. Induction of the mevalonate pathway has been reported as a mechanism of chemoresistance in other cancers; this is the first observation in bladder cancer. Combinations of statins with doxorubicin-containing chemotherapy regimens may provide a therapeutic advantage in such cases.

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“…Although statin use may be associated with a lower risk of bladder cancer [17] or not be associated with bladder cancer [18,19] in white people, a Japanese study did show a significantly higher risk of bladder cancer in pravastatin users [20]. Whether the higher risk associated with statin use (Table 2) was attributable to the effect of statins per se or to a residual effect of severe dyslipidaemia is not known, because patients requiring statin are always under-treated in Taiwan [21] and those receiving statin may have more severe dyslipidaemia.…”

Section: Discussionmentioning

confidence: 99%

Diabetes and risk of bladder cancer: a study using the National Health Insurance database in Taiwan

2011

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Aims/hypothesis Studies on the link between diabetes and bladder cancer in Asians are rare. We investigated the association between diabetes and incidence of bladder cancer by using a large national insurance database. Methods A random sample of 1,000,000 individuals covered by the National Health Insurance was recruited. A total of 495,199 men and 503,748 women for all ages and 187,609 men and 189,762 women ≥40 years old and without bladder cancer at recruitment were followed from 2003 to 2005. Cox regression evaluated the adjusted relative risk for all ages and for age ≥40 years old. Results The results were similar for all ages and for age ≥40 years. In Cox models, patients with diabetes consistently showed a significantly higher relative risk ranging from 1.36 to 1.51 after adjustment for age, sex and other potential confounders. Age, male sex, nephropathy, urinary tract diseases (infection and stone) and statin use were associated with bladder cancer, but occupation, hypertension, stroke, ischaemic heart disease, peripheral arterial disease, eye disease, dyslipidaemia and medications (oral glucose-lowering agents including sulfonylurea, metformin, acarbose and thiazolidinediones, insulin, fibrates, ACE inhibitors/angiotensin receptor blockers and calcium channel blockers) were not. Chronic obstructive pulmonary disease and living in regions other than Metropolitan Taipei were associated with lower risk. Conclusions Patients with diabetes have a higher risk of bladder cancer. The association with urinary tract diseases suggests a complex scenario in the link between bladder cancer and diabetes at different disease stages.

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Statins and Cancer Risk

Cited by 120 publications

References 34 publications

Dysregulation of the mevalonate pathway promotes transformation

Dysregulation of the mevalonate pathway promotes transformation

Establishment and characterization of a bladder cancer cell line with enhanced doxorubicin resistance by mevalonate pathway activation

Diabetes and risk of bladder cancer: a study using the National Health Insurance database in Taiwan

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