Interconnection of Estrogen/Testosterone Metabolism and Mevalonate Pathway in Breast and Prostate Cancers. Hartwell, K. A. et al. Moreover, exogenous expression of cell surface E-cadherin converts statin-sensitive cells to a partially resistant state implying that statin resistance is in part dependent on intact E-cadherin signaling. S10) was without effect. Clipboard, Search History, and several other advanced features are temporarily unavailable. Cell 19, 491505, 10.1016/j.devcel.2010.09.011 (2010). Anti-oxidation and Mitochondrial Damage 2, Rhabdomyolysis - From the London Blitz to Statins, Ten Common Myths about Statins and Cholesterol - 1 of 3, Ten Common Myths about Statins and Cholesterol - 2 of 3, Ten Common Myths about Statins and Cholesterol - 3 of 3. These sensitive cell lines differed in their total E-cadherin content: HOP-92 and SK-MEL-5 cells showed discernible intracellular E-cadherin expression, whereas E-cadherin expression was undetectable in the other four cell lines (Supplementary Fig. After 24-hours incubation, the cells were stained using the cholesterol cell-based detection assay kit (Cayman Chemical) according to the manufacturer's instructions. Authors and JavaScript. Statins are competitive inhibitors of HMG-CoA reductase, thus blocking the progression of the mevalonate pathway and limiting the downstream reactions and accumulation of the final products: cholesterol, isoprenoids, dolichol, ubiquinone, and isopentenyladenine ( Clendening et al., 2010; Thurnher et al., 2012 ). Federal government websites often end in .gov or .mil. We found that atorvastatin affected the proliferation rates of these cancer cell lines differentially: the proliferation of some cell lines were fully or partially inhibited by atorvastatin while others were insensitive to it (Fig. The site is secure. PLoS One. Mevalonate metabolism regulates basal breast cancer stem cells and is a potential therapeutic target. Stem Cell Res. Statins also exert potent additivity or synergy with existing chemotherapeutics. 2021 Jun;52(2):819-821. doi: 10.1007/s12029-021-00644-8. Cordenonsi, M. et al. Cancer Res. In contrast, cell lines that displayed any cell membrane E-cadherin expression were either fully or partially atorvastatin-resistant (Fig. Repurposing existing drugs for new clinical applications is one of the safest and least resource-intensive approaches to improve therapeutic options1,2. And there is no doubt in my mind that many more statin associated problems may be involved with this dolichol function as we gain more knowledge. Tang L, Wei R, Chen R, Fan G, Zhou J, Qi Z, Wang K, Wei Q, Wei X, Xu X. Comput Struct Biotechnol J. The data were analyzed using Student's t-test. 2014 Sep 1;74(17):4772-82. doi: 10.1158/0008-5472.CAN-14-0130. 2014 Nov 6;9(11):e112201. Scientific Reports (Sci Rep) 32, 413419, 10.1097/PAS.0b013e31813547f8 (2008). To study the effect of statins, sufficient Mevacor was used to inhibit the mevalonate pathway of a melanoma cell line thereby arresting the usual DNA mandated cell growth for a period of 24 hours. We show that chemoresistant SCLC undergoes metabolic reprogramming relying on the mevalonate (MVA)-geranylgeranyl diphosphate (GGPP) pathway, which can be targeted using clinically approved statins. While vimentin is a cytoplasmic protein, E-cadherin can be found in different subcellular localizations within tumor cells21,22. S9).The only exception is the HS-578T breast cancer cell line that is only partially atorvastatin sensitive (Fig. Most doctors got an introduction to this in medical school biochemistry classes but by the time of graduation most had forgotten dolichols and their important roles in glycolysis, neuropeptide formation, cell identification and immuno-resistance, if we were ever taught. Representative images from three experiments are shown. -, Borgquist S, Jgi A, Pontn F, Rydn L, Brennan DJ, Jirstrm K (2008) Prognostic impact of tumour-specific HMG-CoA reductase expression in primary breast cancer. Google Scholar. This report focuses on dolichols and why we must be particularly concerned about the consequences of statin damage to this poorly understood, yet extremely important, biochemical function. Defining Coronary Heart Disease Risk What About Cholesterol? wrote the manuscript. Statins and protein prenylation in cancer cell biology and therapy. The next day, cells were treated with 0.1M, 0.3M, 1M, 3M, 10M, or 30M atorvastatin. Cite this article. Gastroenterology. Quantification of the cholesterol levels was accomplished using the Granularity algorithm in the MetaXpress image analysis software (Molecular Devices Corp., Sunnyvale CA). Immediate utility of two approved agents to target both the metabolic mevalonate pathway and its restorative feedback loop. This results in deficient up-regulation of 2 isoforms of hydroxymethylglutaryl coenzyme A reductase: the rate-limiting enzyme of the mevalonate pathway and hydroxymethylglutaryl coenzyme A synthase 1. 2022 Aug 1;20:4402-4414. doi: 10.1016/j.csbj.2022.07.030. Unable to load your collection due to an error, Unable to load your delegates due to an error. Cancer Res. Some of the atorvastatin sensitive cells (HOP-92 and PC-3) were also treated with 100M R-mevalonic acid (Sigma-Aldrich). 2020 Dec 24;2(1):27-59. doi: 10.1002/mco2.27. Results: (function () { Bookshelf 2, Inflammation Key to Heart Disease / Obesity Link, Saturated Fat and Cholesterol - Heart Disease. Front. 4AF). The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder in order to reproduce the material. A representative image of RFP and Ecad cells treated with 3M atorvastatin illustrates this shift (Fig. 4AF). 2021 Oct 29;10(11):1115. doi: 10.3390/biology10111115. After years of studying this subject I now have research documentation for the hundreds of case reports of unusual behavioral manifestations associated with statin use. Statin use was not associated with improved cancer-specific survival in this cohort (HR=0.91, 95% CI 0.64-1.28). Atorvastatin inhibits the enzymatic activity of HMGCR, thus blocking the synthesis of mevalonate and its downstream products that include cholesterol (Supplementary Fig. and Z.N.O. Statin inhibition of HMGCR decreases the levels of mevalonate and its downstream products, including cholesterol, dolichol, ubiquinone and the isoprenoid intermediates geranyl-geranyl pyrophosphate and farnesyl pyrophosphate (Supplementary Fig. Proteins were separated on NuPAGE 412% Bis Tris gel electrophoresis (Life Technologies) and transferred to a nitrocellulose membrane (iBlot Gel Transfer Stacks Nitrocellulose; Life Technologies) using iBlot Gel Transfer Device (Life Technologies). Metabolic alteration of cholesterol synthesis is one pathway that is linked to tumorigenesis and some cancer stem cells and cell lines exhibit increased cholesterol synthesis through the mevalonate pathway5,16. Sorrentino, G. et al. Intracellular cholesterol levels were determined by Filipin III staining. Bhat, K. P. et al. 13, 877883, 10.1038/ncb2303 (2011). Cancer 6, 813823, 10.1038/nrc1951 (2006). Statins have been shown to act through mevalonate-dependent and -independent mechanisms able to affect several tissue functions and modulating specific signal transduction pathways that could account for statin pleiotropic effect. PubMed Statin-induced mevalonate pathway inhibition attenuates the growth of mesenchymal-like cancer cells that lack functional E-cadherin mediated cell cohesion Katsuhiko Warita, Tomoko Warita,. Farwell, W. R. et al. The site is secure. MeSH Statins are potent inhibitors of HMG-CoA reductase, which catalyze formation of mevalonate from HMG-CoA and is the rate-limiting step in the mevalonate and cholesterol biosynthetic pathways . S10). Metabolic control of YAP and TAZ by the mevalonate pathway. ADS 4 Suppl 1S11, 10.1186/scrt372 (2013). Unable to load your collection due to an error, Unable to load your delegates due to an error. As metastasizing tumor cells undergo epithelial to mesenchymal transition (EMT) during the initiation of the metastatic cascade from the primary tumor site18, statin co-therapy may be an effective approach to reduce the metastatic competency of primary tumors and the rate of metastasis formation. Histochemistry 86, 241248 (1987). Natl. Epub 2017 Jun 28. The https:// ensures that you are connecting to the Pharmacol. and a National Science Foundation grant to Z.N.O. The mevalonate pathway synthesizes intermediates and products such as cholesterol and nonsterol isoprenoids that are crucial for cell survival and function. Bengtsson E, Nerjovaj P, Wangefjord S, Nodin B, Eberhard J, Uhln M, Borgquist S, Jirstrm K. Diagn Pathol. Google Scholar. CAS J Natl Cancer Inst. Based on the collected data, the fourteen cell lines were segregated into one of three groups, each with different patterns of vimentin and E-cadherin expression (Fig. Statin use was determined through clinical note review. Major cellular functions depend on isoprenylation including proliferation, migration, metabolism and protein glycosylation that are all crucial for proper development of the embryo and the placenta. Cancer 9, 179, 10.1186/1476-4598-9-179 (2010). & Taylor, D. P. The dormancy dilemma: quiescence versus balanced proliferation. Pharmacological actions of statins: a critical appraisal in the management of cancer. PubMed ADS 324, 112, 10.1016/j.canlet.2012.04.011 (2012). The effects of statins on the mevalonic acid pathway in recombinant yeast strains expressing human HMG-CoA reductase. sharing sensitive information, make sure youre on a federal These transcription factors are not only crucial for normal organ size control and stem cell renewal but also play an important role in inducing tumorigenesis and metastasis29,32, in part by inducing mesenchymal differentiation33, cancer stem cell related traits34 and cancer cell motility30. 111, E8998, 10.1073/pnas.1319190110 (2014). In this study, we show that statins are potential drugs for such a therapeutic purpose. The https:// ensures that you are connecting to the Campbell, M. J. et al. -, Bjarnadottir O, Romero Q, Bendahl P-O, Jirstrm K, Rydn L, Loman N, Uhln M, Johannesson H, Rose C, Grabau D, Borgquist S (2013) Targeting HMG-CoA reductase with statins in a window-of-opportunity breast cancer trial. An official website of the United States government. By comparing the various possible mechanisms of how cell growth could be arrested, they found that 95% of this effect of statins was mediated by the dolichol route. Pharmacol. Careers. Here, we show that statin-induced reduction in intracellular cholesterol levels correlate with the growth inhibition of cancer cell lines upon statin treatment. 2017 Jun 6;116 (12):1652-1659. doi: 10.1038/bjc.2017.139. Recommendations, statements and other opinions expressed on this site have not been evaluated by the U.S. Food and Drug Administration. Reprograming of lipid metabolism includes a deregulated activity of mevalonate (MVA)/cholesterol biosynthetic pathway in specific cancer cells which, in comparison with normal cell counterparts, are dependent of the continuous availability of MVA/cholesterol-derived metabolites (i.e., sterols and non-sterol intermediates) for tumor development. Wells, A., Griffith, L., Wells, J. https://doi.org/10.1038/srep07593. S2) in a dose-dependent manner (Supplementary Fig. Lipid metabolism in cancer progression and therapeutic strategies. In statin-sensitive cell lines, the inhibition of HMGCR likely leads to growth inhibition by at least three different mechanisms. Nielsen, S. F., Nordestgaard, B. G. & Bojesen, S. E. Statin use and reduced cancer-related mortality. To study the effect of statins, sufficient Mevacor was used to inhibit the mevalonate pathway of a melanoma cell line thereby arresting the usual DNA mandated cell growth for a period of 24 hours. 100, 134139, 10.1093/jnci/djm286 (2008). PWH is the Founder and Director in PathXL Ltd. MS-T is a senior advisor to PathXL. Yet, biomarkers that demarcate statin sensitive cancer cell lines have not been truly discerned, hampering their rational development as an adjuvant therapy. This site needs JavaScript to work properly. 2017;10(2):86-114. doi: 10.2174/1874467209666160112125631. This is now a routine laboratory procedure, telling us that researchers have long known of the effect of statins on cell growth. These data indicate that the correlation between mesenchymal marker vimentin and epithelial marker E-cadherin expression cannot be used as dependable biomarker for predicting or identifying atorvastatin sensitive cancer cells. Cell Biol. Three days after treatment, the cells were washed with PBS and fixed in 4% formaldehyde (F79-1, Fisher Scientific) for 15 minutes. Animal studies; mevalonate pathway; placental development; preeclampsia; pregnancy; statins. Cancer Epidemiol. FOIA The cohort consisted of 740 stage II and III colon cancer patients diagnosed between 2004 and 2008. Neoplasia 14, 311323 (2012). The cells were washed with milli-Q water and stained with 0.5% w/v crystal violet (Sigma-Aldrich) for 10 minutes and excess dye was washed extensively with tap water. Alizadeh J et al. Excluding the HS-578T cell line, all partially or fully atorvastatin resistant cell lines express some degree of cell surface E-cadherin (Fig. 4G, Supplementary Fig. The biological perspective. doi: 10.1371/journal.pone.0112201. Genomics 40, 367374, 10.1016/j.jgg.2013.05.002 (2013). Interplay of mevalonate and Hippo pathways regulates RHAMM transcription via YAP to modulate breast cancer cell motility. Future studies will aim at examining the vimentin and E-cadherin expression and functional state of circulating tumors cells. Statin use is not associated with improved progression free survival in cetuximab treated KRAS mutant metastatic colorectal cancer patients: results from the CAIRO2 study. Immunodetection was performed using the iBlot Western Detection chromogenic kit (Life Technologies). gcse.type = 'text/javascript'; We found that mevalonate reversed the atorvastatin-induced growth inhibition of the ten cancer cell lines that displayed full or partial sensitivity to atorvastatin (Fig. Clipboard, Search History, and several other advanced features are temporarily unavailable. Scientific Reports Please enable it to take advantage of the complete set of features! The cells were seeded in 6-well plates at a density of 1 105cells/ml and incubated overnight prior to treating with 10M atorvastatin or 0.1% DMSO, which served as a control. 2017;10(1):6-12. doi: 10.2174/1874467209666160112125805. 8600 Rockville Pike Protein concentration was determined with the bicinchoninic acid (BCA) method (BCA Protein Assay - Reducing Agent Compatible; Thermo Scientific). Epub 2019 Apr 10. Biomarker-guided repurposing of chemotherapeutic drugs for cancer therapy: a novel strategy in drug development. As these two markers are routinely used in standard immunohistochemistry of tumor biopsy specimens, we probed their utility as biomarkers of atorvastatin sensitivity. J Gastrointest Cancer. In the human placenta, the prenylation of proteins, rather than cholesterol synthesis, represents the main "metabolic target" of mevalonate metabolism. Zhao, B., Tumaneng, K. & Guan, K. L. The Hippo pathway in organ size control, tissue regeneration and stem cell self-renewal. Disclaimer, National Library of Medicine An official website of the United States government. The selected cell linescolon cancer (HCT-116 and KM-12), ovarian cancer (IGROV1 and OVCAR3), breast cancer (HS-578T and T47D), lung cancer (HOP-92 and NCI-H322M), prostate cancer (PC-3 and DU-145), melanoma (SK-MEL-5 and MDA-MB-435) and brain cancer (SF-295 and SF-539)were cultured in RPMI 1640 medium (Life Technologies, Grand Island, NY), supplemented with 10% heat-inactivated fetal bovine serum (HI-FBS, Life Technologies) and 1% penicillin/streptomycin (Life Technologies) at 37C with 5% CO2. The degree of vimentin and E-cadherin expression varied among the individual cell lines. Exogenous expression of cell surface E-cadherin converts statin- sensitive cells to a partially resistant state implying that statin resistance is in part dependent on the tumor cells attaining an epithelial phenotype. Abstract The mevalonate pathway in human is responsible for the synthesis of cholesterol and other important biomolecules such as coenzyme Q, dolichols and isoprenoids. The anti-cancer effect of statins may be restricted to certain molecular subgroups. Statins impair glucose uptake in tumor cells. PubMed This determinant of sensitivity further provides molecular rationale for the significant therapeutic index of statins on these tumor cells. Before This research was in part supported by a VA Merit grant and an NCATS-funded Tissue Chip program (TR000496) to A.W. 3 ( 19 ): e112201 enable it to take advantage of the drug did affect ) method ( BCA ) method ( BCA ) method ( BCA ) method ( BCA protein Assay Reducing! L., Shepard, C. K., Knudsen, K. S. & Thompson C.. 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