Mevalonate pathway inhibitors affect anticancer drug-induced cell death and DNA damage response of human sarcoma cells

Nilsson, Sverker; Huelsenbeck, Johannes; Fritz, Gerhard

doi:10.1016/j.canlet.2010.12.022

Cited by 30 publications

(22 citation statements)

References 59 publications

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“…Regarding normal cells, statins exhibit multiple inhibitory effects on stress responses stimulated by anticancer therapeutics. For instance, lovastatin impacts cisplatinand doxorubicin-induced activation of JNK/SAPK [28,29] as well as stimulation of NF-κB following ionizing radiation (IR) and doxorubicin treatment [30,31]. In line with this, statins protect human umbilical vein endothelial cells (HUVEC) from the cytotoxic effects of doxorubicin [28] and radiation damage in vitro [32,33].…”

Section: Introductionmentioning

confidence: 88%

Lovastatin protects keratinocytes from DNA damage-related pro-apoptotic stress responses stimulated by anticancer therapeutics

Ziegler

Albers

Fritz

2016

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Section: Introductionmentioning

confidence: 88%

Lovastatin protects keratinocytes from DNA damage-related pro-apoptotic stress responses stimulated by anticancer therapeutics

Ziegler

Albers

Fritz

2016

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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“…In addition, based on our genetic data, treatment with Statin drugs and H3K4 methyltransferase inhibitors could be an effective drug treatment. Previous work by others suggests that a combinatorial treatment with Statins and additional chemothereputic agents, such as Doxorubicin and Cisplatin, is efficacious (82)(83)(84). Additionally, it is quite possible that treatments for pathogenic fungal infections, such as Candida albicans, could have an increased efficacy using a combination of Statin and a histone H3K4 methyltransferase inhibitor.…”

Section: Discussionmentioning

confidence: 99%

H3K4 methyltransferase Set1 is involved in maintenance of ergosterol homeostasis and resistance to Brefeldin A

South

Harmeyer

Serratore

et al. 2013

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

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Set1 is a conserved histone H3 lysine 4 (H3K4) methyltransferase that exists as a multisubunit complex. Although H3K4 methylation is located on many actively transcribed genes, few studies have established a direct connection showing that loss of Set1 and H3K4 methylation results in a phenotype caused by disruption of gene expression. In this study, we determined that cells lacking Set1 or Set1 complex members that disrupt H3K4 methylation have a growth defect when grown in the presence of the antifungal drug Brefeldin A (BFA), indicating that H3K4 methylation is needed for BFA resistance. To determine the role of Set1 in BFA resistance, we discovered that Set1 is important for the expression of genes in the ergosterol biosynthetic pathway, including the rate-limiting enzyme HMG-CoA reductase. Consequently, deletion of SET1 leads to a reduction in HMG-CoA reductase protein and total cellular ergosterol. In addition, the lack of Set1 results in an increase in the expression of DAN1 and PDR11, two genes involved in ergosterol uptake. The increase in expression of uptake genes in set1Δ cells allows sterols such as cholesterol and ergosterol to be actively taken up under aerobic conditions. Interestingly, when grown in the presence of ergosterol set1Δ cells become resistant to BFA, indicating that proper ergosterol levels are needed for antifungal drug resistance. These data show that H3K4 methylation impacts gene expression and output of a biologically and medically relevant pathway and determines why cells lacking H3K4 methylation have antifungal drug sensitivity.chromatin | gene regulation | histone methylation | epigenetics M odifications on histones, such as phosphorylation, acetylation, methylation, and ubiquitination, have been implicated in gene expression and silencing (1, 2). One modification on histone H3 that is associated with active gene expression is the methylation of lysine 4 (H3K4) (3, 4). H3K4 methylation is present concurrently in mono-, di-, and trimethyl forms in the cell (1, 2). Primarily, H3K4 methylation is maintained in a pattern that has trimethylation enriched at the 5′ end of ORFs, dimethylation throughout the gene, and monomethylation enriched near the 3′ end (3, 4). In humans, H3K4 methylation is mediated by methyltransferases MLL1-4 and Set1A and -B complexes, which are homologous to the yeast Set1 H3K4 methyltransferase complex (5-12). In addition, Set1 and the human homologs are known to interact with the Ser5-phosphorylated C-terminal tail domain of RNA polymerase II (3). More recently, di-and trimethylated H3K4 have been shown to be docking sites for chromodomain and plant homeodomain (PHD) fingercontaining proteins (1,13,14). Taken together, this and other studies suggest that the methylation of histone H3K4 plays a role in mediating gene expression by recruiting effector proteins.In Saccharomyces cerevisiae, the Set1 complex (Set1C or COMPASS) is responsible for the methylation of histone H3K4 and the kinetochore protein Dam1 (5,[15][16][17][18][19]. Loss of the catalytic protei...

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“…The energy status of the cell is a crucial factor in all aspects of cell function; it is possible that AMPK has many downstream targets whose phosphorylation mediates dramatic changes in cell metabolism, cell growth, and other functions. The potent AMPK activator, metformin, has been demonstrated as an effective antitumor agent through induction DNA damage and apoptosis in osteosarcoma (14). GSK3b, a serine/threonine protein kinase, also plays key roles in multiple pathways.…”

Section: Discussionmentioning

confidence: 99%

“…5-Aminoimidazole-4-carboxamide riboside (AICAR) and metformin are pharmacologically active, potent AMPK activators and have become the focus of much research in carcinogenesis due to their regulation of various signaling pathways, such as the inhibition of mTOR signaling and blocking of the growth of glioblastoma cells that express the activated EGFR mutant, as well as their ability to control the levels of p53, p21, cyclin D1, and caspases (12,13). In addition, metformin has been found to be an effective antitumor agent due to induction of DNA damage and apoptosis in osteosarcoma (14).…”

Section: Introductionmentioning

confidence: 99%

Dihydromyricetin Activates AMP-Activated Protein Kinase and P38MAPK Exerting Antitumor Potential in Osteosarcoma

Zhao

Yin

et al. 2014

Cancer Prevention Research

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Numerous patients with osteosarcoma either are not sensitive to chemotherapy or develop drug resistance to current chemotherapy regimens. Therefore, it is necessary to develop several potentially useful therapeutic agents. Dihydromyricetin is the major flavonoid component derived from Ampelopsis grossedentata, which has a long history of use in food and medicine. The present study examined the antitumor activity both in vitro and in vivo without noticeable side effects and the underlying mechanism of action of dihydromyricetin in osteosarcoma cells. We found that dihydromyricetin induced increased p21 expression and G 2 -M cellcycle arrest, caused DNA damage, activated ATM-CHK2-H2AX signaling pathways, and induced apoptosis in osteosarcoma cells as well as decreasing the sphere formation capability by downregulating Sox2 expression. Mechanistic analysis showed that the antitumor potential of dihydromyricetin may be due to the activation of AMPKa and p38 MAPK , as the activating AMPKa led to the inactivation of GSK3b in osteosarcoma cells. Moreover, GSK3b deletion or GSK3b inhibition by LiCl treatment resulted in increased p21 expression and reduced Sox2 expression in osteosarcoma cells. Taken together, our results strongly indicate that the antitumor potential of dihydromyricetin is correlated with P38 MAPK and the AMPKaGSK3b-Sox2 signaling pathway. Finally, immunohistochemical analysis indicated that some patients had a lower p-AMPK expression after chemotherapy, which supports that the combination of dihydromyricetin and chemotherapy drug will be beneficial for patients with osteosarcoma. In conclusion, our results are the first to suggest that dihydromyricetin may be a therapeutic candidate for the treatment of osteosarcoma. Cancer Prev Res; 7(9); 927-38. Ó2014 AACR.

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Mevalonate pathway inhibitors affect anticancer drug-induced cell death and DNA damage response of human sarcoma cells

Cited by 30 publications

References 59 publications

Lovastatin protects keratinocytes from DNA damage-related pro-apoptotic stress responses stimulated by anticancer therapeutics

Lovastatin protects keratinocytes from DNA damage-related pro-apoptotic stress responses stimulated by anticancer therapeutics

H3K4 methyltransferase Set1 is involved in maintenance of ergosterol homeostasis and resistance to Brefeldin A

Dihydromyricetin Activates AMP-Activated Protein Kinase and P38MAPK Exerting Antitumor Potential in Osteosarcoma

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