Simvastatin exerts anticancer effects in osteosarcoma cell lines via geranylgeranylation and c-Jun activation

Kany, Shinwan; Woschek, Mathias; Kneip, Niels; Sturm, Ramona; Kalbitz, Miriam; Hanschen, Marc; Relja, Borna

doi:10.3892/ijo.2018.4288

Cited by 26 publications

(21 citation statements)

References 55 publications

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“…As statins have long been safely used to treat hypercholesterolemia and prevent cardiovascular diseases, they may hold promise as anti-metastatic treatment of cancers, in which YAP/TAZ play an important role [254]. In fact, simvastatin has been demonstrated to exert antimetastatic and cytotoxic effects in osteosarcoma [255,256], at least in part by the downregulation of YAP/TAZ/TEAD target genes CYR61 and CTGF [257,258]. It has also been shown to reactivate YAP-suppressed SOX9 in rat chondrosarcoma cells, leading to chondrocytic re-differentiation [259].…”

Section: Resultsmentioning

confidence: 99%

The YAP/TAZ Pathway in Osteogenesis and Bone Sarcoma Pathogenesis

Kovar

Bierbaumer

Radic-Sarikas

2020

Cells

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YAP and TAZ are intracellular messengers communicating multiple interacting extracellular biophysical and biochemical cues to the transcription apparatus in the nucleus and back to the cell/tissue microenvironment interface through the regulation of cytoskeletal and extracellular matrix components. Their activity is negatively and positively controlled by multiple phosphorylation events. Phenotypically, they serve an important role in cellular plasticity and lineage determination during development. As they regulate self-renewal, proliferation, migration, invasion and differentiation of stem cells, perturbed expression of YAP/TAZ signaling components play important roles in tumorigenesis and metastasis. Despite their high structural similarity, YAP and TAZ are functionally not identical and may play distinct cell type and differentiation stage-specific roles mediated by a diversity of downstream effectors and upstream regulatory molecules. However, YAP and TAZ are frequently looked at as functionally redundant and are not sufficiently discriminated in the scientific literature. As the extracellular matrix composition and mechanosignaling are of particular relevance in bone formation during embryogenesis, post-natal bone elongation and bone regeneration, YAP/TAZ are believed to have critical functions in these processes. Depending on the differentiation stage of mesenchymal stem cells during endochondral bone development, YAP and TAZ serve distinct roles, which are also reflected in bone tumors arising from the mesenchymal lineage at different developmental stages. Efforts to clinically translate the wealth of available knowledge of the pathway for cancer diagnostic and therapeutic purposes focus mainly on YAP and TAZ expression and their role as transcriptional co-activators of TEAD transcription factors but rarely consider the expression and activity of pathway modulatory components and other transcriptional partners of YAP and TAZ. As there is a growing body of evidence for YAP and TAZ as potential therapeutic targets in several cancers, we here interrogate the applicability of this concept to bone tumors. To this end, this review aims to summarize our current knowledge of YAP and TAZ in cell plasticity, normal bone development and bone cancer.Cells 2020, 9, 972 2 of 34 co-activators Yes-associated protein 1 (YAP-1, YAP) and its paralogue, the transcriptional co-activator with PDZ-binding motif (TAZ, WWTR1), which are typically controlled on the post-translational level by upstream regulatory signaling pathways in organ development and tissue homeostasis [2,3]. YAP and TAZ were reported to affect self-renewal and lineage commitment of stem cells [4][5][6][7], while hyperactivation of YAP and TAZ have been linked to cancer growth and metastasis in various tumors [8][9][10]. TAZ levels are elevated in approximately 20% of cancers and drive invasion and metastasis [11,12], while YAP is frequently overexpressed or amplified in cancer and was shown to promote resistance to chemotherapy in oncogene-addicted tumors up...

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Section: Resultsmentioning

confidence: 99%

The YAP/TAZ Pathway in Osteogenesis and Bone Sarcoma Pathogenesis

Kovar

Bierbaumer

Radic-Sarikas

2020

Cells

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“…Statins have been extensively tested in humans, as they are widely used in hypercholesterolemia treatment. Moreover, previous observations in human and murine OS cells showed that statins sensitize OS cells to anticancer drugs and synergistically act with chemotherapeutic agents to reduce cell invasiveness [44,45]. Here, we focused on the role of prelamin A in statin-dependent effects.…”

Section: Discussionmentioning

confidence: 98%

Lamin A and Prelamin A Counteract Migration of Osteosarcoma Cells

Evangelisti

Paganelli

Giuntini

et al. 2020

Cells

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A type lamins are fundamental components of the nuclear lamina. Changes in lamin A expression correlate with malignant transformation in several cancers. However, the role of lamin A has not been explored in osteosarcoma (OS). Here, we wanted to investigate the role of lamin A in normal osteoblasts (OBs) and OS cells. Thus, we studied the expression of lamin A/C in OS cells compared to OBs and evaluated the effects of lamin A overexpression in OS cell lines. We show that, while lamin A expression increases during osteoblast differentiation, all examined OS cell lines express lower lamin A levels relative to differentiated OBs. The condition of low LMNA expression confers to OS cells a significant increase in migration potential, while overexpression of lamin A reduces migration ability of OS cells. Moreover, overexpression of unprocessable prelamin A also reduces cell migration. In agreement with the latter finding, OS cells which accumulate the highest prelamin A levels upon inhibition of lamin A maturation by statins, had significantly reduced migration ability. Importantly, OS cells subjected to statin treatment underwent apoptotic cell death in a RAS-independent, lamin A-dependent manner. Our results show that pro-apoptotic effects of statins and statin inhibitory effect on OS cell migration are comparable to those obtained by prelamin A accumulation and further suggest that modulation of lamin A expression and post-translational processing can be a tool to decrease migration potential in OS cells.

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“…The small sample size certainly limits the statistical power of the study. The study design and the sample size are based on previous in vitro studies from our group ( 22 , 50 ), and the observed significant results upon stimulation with cytokines as compared to unstimulated controls in the present study. Additionally, other relevant pro- and anti-inflammatory cytokines should be included in further analyses.…”

Section: Discussionmentioning

confidence: 99%

Suppression of the interleukin-1β-induced inflammatory response of human Chang liver cells by acute and subacute exposure to alcohol: an in vitro study

Mörs¹,

Kany²,

Hörauf³

et al. 2018

Croat Med J

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AimTo evaluate protective immunosuppressive dose and time-dependent effects of ethanol in an in vitro model of acute inflammation in human Chang liver cells.MethodThe study was performed in 2016 and 2017 in the research laboratory of the Department of Trauma, Hand and Reconstructive Surgery, the University Hospital of the Goethe-University Frankfurt. Chang liver cells were stimulated with either interleukin (IL)-1β or IL-6 and subsequently treated with low-dose ethanol (85 mmol/L) or high-dose ethanol (170 mmol/L) for one hour (acute exposure) or 72 hours (subacute exposure). IL-6 and IL-1β release were determined by enzyme-linked immunosorbent assay. Neutrophil adhesion to Chang liver monolayers, production of reactive oxygen species, and apoptosis or necrosis were analyzed.ResultsContrary to high-dose ethanol, acute low-dose ethanol exposure significantly reduced IL-1β-induced IL-6 and IL-6-induced IL-1β release (P < 0.05). Subacute ethanol exposure did not change proinflammatory cytokine release. Acute low-dose ethanol exposure significantly decreased inflammation-induced formation of reactive oxygen species (P < 0.05) and significantly improved cell survival (P < 0.05). Neither acute nor subacute high-dose ethanol exposure significantly changed inflammation-induced changes in reactive oxygen species or survival. Acute and subacute ethanol exposure, independently of the dose, significantly decreased neutrophil adhesion to inflamed Chang liver cells (P < 0.05).ConclusionAcute treatment of inflamed Chang liver cells with ethanol showed its immunosuppressive potential. However, the observed effects were limited to low-dose setting, indicating the relevance of ethanol dose in the modulation of inflammatory cell response.

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Simvastatin exerts anticancer effects in osteosarcoma cell lines via geranylgeranylation and c-Jun activation

Cited by 26 publications

References 55 publications

The YAP/TAZ Pathway in Osteogenesis and Bone Sarcoma Pathogenesis

The YAP/TAZ Pathway in Osteogenesis and Bone Sarcoma Pathogenesis

Lamin A and Prelamin A Counteract Migration of Osteosarcoma Cells

Suppression of the interleukin-1β-induced inflammatory response of human Chang liver cells by acute and subacute exposure to alcohol: an in vitro study

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