The tumor suppressor geneARHI(DIRAS3)inhibits ovarian cancer cell migration through multiple mechanisms

Lü, Zhen; Bast, Robert C.

doi:10.4161/cam.23648

Cited by 31 publications

(24 citation statements)

References 65 publications

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“…Our findings are consistent with data showing a negative correlation between EPCAM and ZEB1 in several cancer cell lines (47, 48). The roles of JAM-A, DIRAS3 and MARVELD3 as potential tumor suppressors and promoters of epithelial phenotype have been previously described (49–51). To the best of our knowledge, this is the first report on the negative correlation between ZEB1 and JAM-A, DIRAS3 and MARVELD3.…”

Section: Discussionmentioning

confidence: 96%

Novel Strategies to Enforce an Epithelial Phenotype in Mesenchymal Cells

Dragoi¹,

Swiss²,

Gao³

et al. 2014

Cancer Research

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E-cadherin downregulation in cancer cells is associated with epithelial-to-mesenchymal transition (EMT) and metastatic prowess, but the underlying mechanisms are incompletely characterized. In this study, we probed E-cadherin expression at the plasma membrane as a functional assay to identify genes involved in E-cadherin downregulation. The assay was based on the E-cadherin-dependent invasion properties of the intracellular pathogen Listeria monocytogenes. On the basis of a functional readout, automated microscopy and computer-assisted image analysis were used to screen siRNAs targeting 7,000 human genes. The validity of the screen was supported by its definion of several known regulators of E-cadherin expression, including ZEB1, HDAC1 and MMP14. We identified three new regulators (FLASH, CASP7 and PCGF1), the silencing of which was sufficient to restore high levels of E-cadherin transcription. Additionally, we identified two new regulators (FBXL5 and CAV2), the silencing of which was sufficient to increase E-cadherin expression at a post-transcriptional level. FLASH silencing regulated the expression of E-cadherin and other ZEB1-dependent genes, through post-transcriptional regulation of ZEB1, but it also regulated the expression of numerous ZEB1-independent genes with functions predicted to contribute to a restoration of the epithelial phenotype. Finally, we also report the identification of siRNA duplexes that potently restored the epithelial phenotype by mimicking the activity of known and putative microRNAs. Our findings suggest new ways to enforce epithelial phenotypes as a general strategy to treat cancer by blocking invasive and metastatic phenotypes associated with EMT.

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Section: Discussionmentioning

confidence: 96%

Novel Strategies to Enforce an Epithelial Phenotype in Mesenchymal Cells

Dragoi¹,

Swiss²,

Gao³

et al. 2014

Cancer Research

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“…Studies have shown that ARHI inhibits cell growth in HOC and that loss of ARHI expression contributes to the formation of HOC 11. When ARHI re-expression was promoted using demethylation factors and histone deacetylase inhibitors in different tissues, tumor growth rates were reduced, and apoptosis increased 12.…”

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confidence: 99%

S-Phase Cell Cycle Arrest, Apoptosis, and Molecular Mechanisms of Aplasia Ras homolog Member I–Induced Human Ovarian Cancer SKOV3 Cell Lines

Zhu

Meng

et al. 2014

Int J Gynecol Cancer

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ObjectiveAplasia Ras homolog member I (ARHI) is associated with human ovarian cancer (HOC) growth and proliferation; however, the mechanisms are unclear. The purpose of this study was to investigate ARHI effects in HOC SKOV3 cells.MethodsWe transfected SKOV3 cells with PIRES2-EGFP-ARHI and measured growth inhibition rates, cell cycle distribution, apoptosis rates, and expression of P-STAT3 (phosphorylated signal transduction and activators of transcription 3) and P-ERK (phosphorylated extracellular signal regulated protein kinase).ResultsOur data showed significant inhibition of growth, significantly increased S-phase arrest and apoptosis rates, and reduction of P-STAT3 and P-ERK1/2 expression levels.ConclusionsWe propose the mechanism may involve ARHI-induced phosphorylation of ERK1/2 and STAT3 protein kinases, thereby blocking proliferation signaling pathways, to induce HOC SKOV3 apoptosis.

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“…6b and d). Alternatively, ARHI expression has also been shown to alter the subcellular localization of STAT3 [25] which plays an important role in maintaining the activity of Complex I and II in the electron transport chain [26]. Either of these mechanisms could explain the observed bioenergetic shock although additional experiments are necessary to determine which (if any) of these are relevant in the ARHI model.…”

Section: Discussionmentioning

confidence: 99%

Induction of autophagy by ARHI (DIRAS3) alters fundamental metabolic pathways in ovarian cancer models

et al. 2016

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BackgroundAutophagy is a bulk catabolic process that modulates tumorigenesis, therapeutic resistance, and dormancy. The tumor suppressor ARHI (DIRAS3) is a potent inducer of autophagy and its expression results in necroptotic cell death in vitro and tumor dormancy in vivo. ARHI is down-regulated or lost in over 60 % of primary ovarian tumors yet is dramatically up-regulated in metastatic disease. The metabolic changes that occur during ARHI induction and their role in modulating death and dormancy are unknown.MethodsWe employed Nuclear Magnetic Resonance (NMR)-based metabolomic strategies to characterize changes in key metabolic pathways in both cell culture and xenograft models of ARHI expression and autophagy. These pathways were further interrogated by cell-based immunofluorescence imaging, tracer uptake studies, targeted metabolic inhibition, and in vivo PET/CT imaging.ResultsInduction of ARHI in cell culture models resulted in an autophagy-dependent increase in lactate production along with increased glucose uptake and enhanced sensitivity to glycolytic inhibitors. Increased uptake of glutamine was also dependent on autophagy and dramatically sensitized cultured ARHI-expressing ovarian cancer cell lines to glutaminase inhibition. Induction of ARHI resulted in a reduction in mitochondrial respiration, decreased mitochondrial membrane potential, and decreased Tom20 staining suggesting an ARHI-dependent loss of mitochondrial function. ARHI induction in mouse xenograft models resulted in an increase in free amino acids, a transient increase in [18F]-FDG uptake, and significantly altered choline metabolism.ConclusionsARHI expression has previously been shown to trigger autophagy-associated necroptosis in cell culture. In this study, we have demonstrated that ARHI expression results in decreased cellular ATP/ADP, increased oxidative stress, and decreased mitochondrial function. While this bioenergetic shock is consistent with programmed necrosis, our data indicates that the accompanying up-regulation of glycolysis and glutaminolysis is autophagy-dependent and serves to support cell viability rather than facilitate necroptotic cell death. While the mechanistic basis for metabolic up-regulation following ARHI induction is unknown, our preliminary data suggest that decreased mitochondrial function and increased metabolic demand may play a role. These alterations in fundamental metabolic pathways during autophagy-associated necroptosis may provide the basis for new therapeutic strategies for the treatment of dormant ovarian tumors.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2850-8) contains supplementary material, which is available to authorized users.

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The tumor suppressor geneARHI(DIRAS3)inhibits ovarian cancer cell migration through multiple mechanisms

Cited by 31 publications

References 65 publications

Novel Strategies to Enforce an Epithelial Phenotype in Mesenchymal Cells

Novel Strategies to Enforce an Epithelial Phenotype in Mesenchymal Cells

S-Phase Cell Cycle Arrest, Apoptosis, and Molecular Mechanisms of Aplasia Ras homolog Member I–Induced Human Ovarian Cancer SKOV3 Cell Lines

Induction of autophagy by ARHI (DIRAS3) alters fundamental metabolic pathways in ovarian cancer models

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