Biomarker identification for statin sensitivity of cancer cell lines

Raghu, Vineet K.; Beckwitt, Colin H.; Warita, Katsuhiko; Wells, Alan; Benos, Panayiotis V.; Oltvai, Zoltán N.

doi:10.1016/j.bbrc.2017.11.065

Cited by 43 publications

(39 citation statements)

References 25 publications

(28 reference statements)

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“…As reported previously [ 33 ], HMGCR levels are maintained by the feedback response that upregulates both HMGCR mRNA and low-density lipoprotein (LDL)-receptors (LDLR) that enables cholesterol uptake from the serum-containing media; thus alteration in HMGCR protein is not evident as cholesterol homeostasis has been achieved, even in response to statins that do trigger an anti-proliferative response. Treatment with another statin, rosuvastatin, which does not inhibit the growth of DU-145 cells [ 30 ], yielded the same result ( Supplementary Figure 2C, 2E ).…”

Section: Resultssupporting

confidence: 55%

“…We have shown previously that the sensitivity of cancer cell lines to statins’ growth inhibitory effect varies significantly, ranging from highly statin sensitive mesenchymal- to less statin sensitive epithelial and mixed epithelial-mesenchymal cells [ 27 , 30 ]. The differential effect of statins on cancer cells may be due to different effects on the expression or subcellular distribution of their target enzyme, HMGCR (Figure 1 ), or due to additional off-target effects of statins.…”

Section: Resultsmentioning

confidence: 99%

“…We determined membrane E-cadherin to be a resistance marker for statin-mediated growth inhibition and demonstrated that the exogenous expression of membrane E-cadherin in a statin-sensitive cell line was sufficient to decrease statin potency [ 27 ]. We also developed a computational approach to predict drugs that may potentiate statin effects and identified several drugs that may orthogonally improve the growth inhibitory effect of statins in these cells [ 30 ]. However, we have not developed approaches to overcome the relative statin resistance of epithelial and mixed epithelial-mesenchymal cells that comprise dormant and reactivated micrometastases.…”

Section: Discussionmentioning

confidence: 99%

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Concomitant attenuation of HMG-CoA reductase expression potentiates the cancer cell growth-inhibitory effect of statins and expands their efficacy in tumor cells with epithelial characteristics

et al. 2018

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HMG-CoA reductase (HMGCR) inhibitors, statins, are potent cholesterol reducing drugs that exhibit anti-tumor effects in vitro and in animal models, including attenuation of metastasis formation, and their use correlates with reduced cancer-specific mortality in retrospective human cohort studies. However, E-cadherin expressing epithelial- and mixed epithelial-mesenchymal cancer cell lines (reflective of primary and outgrowing metastatic tumor cells, respectively) require higher statin concentrations than mesenchymal-like tumor cells (reflective of in-circulation metastatic tumor cells) to achieve the same degree of growth inhibition. Here, we show that attenuation of HMGCR expression in the presence of atorvastatin leads to stronger growth inhibition than dual target blockade of the mevalonate pathway in relatively statin resistant cell lines, mainly through inhibition of protein prenylation pathways. Thus, combined inhibition of the mevalonate pathway's rate-limiting enzyme, HMGCR, can improve atorvastatin's growth inhibitory effect on epithelial- and mixed mesenchymal-epithelial cancer cells, a finding that may have implications for the design of future anti-metastatic cancer therapies.

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Section: Resultssupporting

confidence: 55%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Concomitant attenuation of HMG-CoA reductase expression potentiates the cancer cell growth-inhibitory effect of statins and expands their efficacy in tumor cells with epithelial characteristics

et al. 2018

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“…Not only did the individual effects among the used statins differ, but also the sensitivity of the used cell lines, which is a known phenomenon in human cancer cell lines [ 52 , 76 , 77 ]. This could be due to differences in the molecular profile of A2780 and IGROV-1 cells.…”

Section: Discussionmentioning

confidence: 99%

Anti-tumor effects of mevalonate pathway inhibition in ovarian cancer

et al. 2020

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Background Ovarian cancer remains the most fatal gynecological malignancy. Current therapeutic options are limited due to late diagnosis in the majority of the cases, metastatic spread to the peritoneal cavity and the onset of chemo-resistance. Thus, novel therapeutic approaches are required. Statins and amino-bisphosphonates are inhibitors of the mevalonate pathway, which is a fundamental pathway of cellular metabolism, essential for cholesterol production and posttranslational protein farnesylation and geranylgeranylation. While this pathway has emerged as a promising treatment target in several human malignancies, its potential as a therapeutic approach in ovarian cancer is still not fully understood. Methods Human ovarian cancer cell lines (IGROV-1, A2780, A2780cis) were treated with increasing concentrations (0.5-100 μM) of statins (simvastatin, atorvastatin, rosuvastatin) and zoledronic acid. Effects on cell vitality and apoptosis were assessed using Cell Titer Blue®, Caspase 3/7 Glo®, clonogenic assays as well as cleaved poly (ADP-ribose) polymerase (cPARP) detection. The inhibition of the mevalonate pathway was confirmed using Western Blot of unprenylated Ras and Rap1a proteins. Quantitative real-time PCR and ELISA were used to analyze modulations on several key regulators of ovarian cancer tumorigenesis. Results The treatment of IGROV-1 and A2780 cells with statins and zoledronic acid reduced vitality (by up to 80%; p < 0.001) and induced apoptosis by up to 8-folds ( p < 0.001) in a dose-dependent fashion. Rescue experiments using farnesyl pyrophosphate or geranylgeranyl pyrophosphate evidenced that blocked geranylgeranylation is the major underlying mechanism of the pro-apoptotic effects. Gene expression of the tumor-promoting cytokines and mediators, such as transforming growth factor (TGF)-β1, vascular endothelial growth factor (VEGF), interleukin (IL)-8, and IL-6 were significantly suppressed by statins and zoledronic acid by up to 90% ( p < 0.001). For all readouts, simvastatin was most potent of all agents used. Cisplatin-resistant A2780cis cells showed a relative resistance to statins and zoledronic acid. However, similar to the effects in A2780 cells, simvastatin and zoledronic acid significantly induced caspase 3/7 activation (6-folds; p < 0.001). Conclusion Our in vitro findings point to promising anti-tumor effects of statins and zoledronic acid in ovarian cancer and warrant additional validation in preclinical and clinical settings.

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“…Rewired lipid metabolism is now considered a hallmark of cancer, and enhanced lipid uptake and lipogenesis are well documented in many cancers and facilitate tumorigenesis 27 . Cholesterol-reducing statins have been reported to suppress tumor cell proliferation 28 . Moreover, clinical studies have demonstrated reduced cancer-specific mortality in patients taking statins 29 .…”

Section: Discussionmentioning

confidence: 99%

Wnt signaling mediates oncogenic synergy between Akt and Dlx5 in T-cell lymphomagenesis by enhancing cholesterol synthesis

Tan

Sementino

Liu

et al. 2020

Sci Rep

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The Dlx5 homeobox gene was first implicated as an oncogene in a T-ALL mouse model expressing myristoylated (Myr) Akt2. Furthermore, overexpression of Dlx5 was sufficient to drive T-ALL in mice by directly activating Akt and Notch signaling. These findings implied that Akt2 cooperates with Dlx5 in T-cell lymphomagenesis. To test this hypothesis, Lck-Dlx5;Lck-MyrAkt2 transgenic mice were generated. MyrAkt2 synergized with Dlx5 to greatly accelerate and enhance the dissemination of T-lymphomagenesis. RNA-seq analysis performed on lymphomas from Lck-Dlx5;Lck-MyrAkt mice revealed upregulation of genes involved in the Wnt and cholesterol biosynthesis pathways. Combined RNA-seq and ChIP-seq analysis of lymphomas from Lck-Dlx5;Lck-MyrAkt mice demonstrated that β-catenin directly regulates genes involved in sterol regulatory element binding transcription factor 2 (Srebf2)-cholesterol synthesis. These lymphoma cells had high Lef1 levels and were highly sensitive to β-catenin and Srebf2-cholesterol synthesis inhibitors. Similarly, human T-ALL cell lines with activated NOTCH and AKT and elevated LEF1 levels were sensitive to inhibition of β-catenin and cholesterol pathways. Furthermore, LEF1 expression positively correlated with expression of genes involved in the cholesterol synthesis pathway in primary human T-ALL specimens. Together, these data suggest that targeting β-catenin and/or cholesterol biosynthesis, together with AKT, could have therapeutic efficacy in a subset of T-ALL patients.

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Biomarker identification for statin sensitivity of cancer cell lines

Cited by 43 publications

References 25 publications

Concomitant attenuation of HMG-CoA reductase expression potentiates the cancer cell growth-inhibitory effect of statins and expands their efficacy in tumor cells with epithelial characteristics

Concomitant attenuation of HMG-CoA reductase expression potentiates the cancer cell growth-inhibitory effect of statins and expands their efficacy in tumor cells with epithelial characteristics

Anti-tumor effects of mevalonate pathway inhibition in ovarian cancer

Wnt signaling mediates oncogenic synergy between Akt and Dlx5 in T-cell lymphomagenesis by enhancing cholesterol synthesis

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