Endoplasmic Reticulum Stress, the Unfolded Protein Response, Autophagy, and the Integrated Regulation of Breast Cancer Cell Fate

Clarke, Robert; Cook, Katherine L.; Hu, Rong; Facey, Caroline O.; Tavassoly, Iman; Schwartz, Jessica L.; Baumann, William T.; Tyson, John J.; Xuan, Jianhua; Wang, Yue; Wärri, Anni; Shajahan, Ayesha N.

doi:10.1158/0008-5472.can-11-3213

Cited by 189 publications

(190 citation statements)

References 126 publications

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“…4) is surprising. In an attempt to reconcile our findings with the vast literature on the role of CIN in cancer, we propose a modification of the current view: As culture conditions may impose stress on primary cells, it is hypothesized that polyploidization is one possible response, out of many (44)(45)(46)(47), to environmental insults. We propose a putative function of polyploidy in counteracting malignancy under environmental stress, such as that imposed on the liver cell population in vivo or on cells in ex vivo culture (Fig.…”

Section: Discussionmentioning

confidence: 80%

Polyploidization of Murine Mesenchymal Cells Is Associated with Suppression of the Long Noncoding RNA H19 and Reduced Tumorigenicity

et al. 2012

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Mesenchymal stromal cells (MSC) are used extensively in clinical trials; however, the possibility that MSCs have a potential for malignant transformation was raised. We examined the genomic stability versus the tumorforming capacity of multiple mouse MSCs. Murine MSCs have been shown to be less stable and more prone to malignant transformation than their human counterparts. A large series of independently isolated MSC populations exhibited low tumorigenic potential under syngeneic conditions, which increased in immunocompromised animals. Unexpectedly, higher ploidy correlated with reduced tumor-forming capacity. Furthermore, in both cultured MSCs and primary hepatocytes, polyploidization was associated with a dramatic decrease in the expression of the long noncoding RNA H19. Direct knockdown of H19 expression in diploid cells resulted in acquisition of polyploid cell traits. Moreover, artificial tetraploidization of diploid cancer cells led to a reduction of H19 levels, as well as to an attenuation of the tumorigenic potential. Polyploidy might therefore serve as a protective mechanism aimed at reducing malignant transformation through the involvement of the H19 regulatory long noncoding RNA. Cancer Res; 72(24); 6403-13. Ó2012 AACR.

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Section: Discussionmentioning

confidence: 80%

Polyploidization of Murine Mesenchymal Cells Is Associated with Suppression of the Long Noncoding RNA H19 and Reduced Tumorigenicity

et al. 2012

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“…(iv) Restoration of the translation arrest in ARIH1-depleted cells experiencing genotoxic stress by preventing formation of a preinitiation complex through inhibition of eIF2 also restores cell survival. (56). Yet another way to arrest mRNA translation is through enhanced mRNA 5= cap binding of eIF4E2, also known as 4EHP (57).…”

Section: Discussionmentioning

confidence: 99%

“…As mentioned above, an alternative route to attenuate protein synthesis is through eIF2␣ Ser51 phosphorylation, a modification typically triggered by an accumulation of misfolded proteins in the ER (56). This response can be enhanced by salubrinal, an inhibitor of the phosphatase complex that dephosphorylates eIF2␣ (64).…”

Section: Discussionmentioning

confidence: 99%

The E3 Ubiquitin Ligase ARIH1 Protects against Genotoxic Stress by Initiating a 4EHP-Mediated mRNA Translation Arrest

Stechow

Typas

Carreras-Puigvert

et al. 2015

Molecular and Cellular Biology

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bDNA damage response signaling is crucial for genome maintenance in all organisms and is corrupted in cancer. In an RNA interference (RNAi) screen for (de)ubiquitinases and sumoylases modulating the apoptotic response of embryonic stem (ES) cells to DNA damage, we identified the E3 ubiquitin ligase/ISGylase, ariadne homologue 1 (ARIH1). Silencing ARIH1 sensitized ES and cancer cells to genotoxic compounds and ionizing radiation, irrespective of their p53 or caspase-3 status. Expression of wild-type but not ubiquitinase-defective ARIH1 constructs prevented sensitization caused by ARIH1 knockdown. ARIH1 protein abundance increased after DNA damage through attenuation of proteasomal degradation that required ATM signaling. Accumulated ARIH1 associated with 4EHP, and in turn, this competitive inhibitor of the eukaryotic translation initiation factor 4E (eIF4E) underwent increased nondegradative ubiquitination upon DNA damage. Genotoxic stress led to an enrichment of ARIH1 in perinuclear, ribosome-containing regions and triggered 4EHP association with the mRNA 5= cap as well as mRNA translation arrest in an ARIH1-dependent manner. Finally, restoration of DNA damage-induced translation arrest in ARIH1-depleted cells by means of an eIF2 inhibitor was sufficient to reinstate resistance to genotoxic stress. These findings identify ARIH1 as a potent mediator of DNA damage-induced translation arrest that protects stem and cancer cells against genotoxic stress. DNA damage leads to acute toxicity and the accumulation of mutations and chromosomal instability, potentially resulting in malignant transformation (1, 2). To counteract these deleterious effects of DNA damage, the cell is equipped with a highly complex signaling response termed the DNA damage response (DDR). The DDR activates effector components involved in protective pathways, including DNA damage repair, cell cycle arrest, transcription regulation, chromatin remodeling, and cell death (1). The complex of DDR signaling pathways is crucial for the protection of the genome in all organisms. Moreover, understanding DDR signaling in the context of chemical or ionizing radiation-induced DNA damage is important to design improved strategies to combat therapy resistance. In tandem with phosphorylation-mediated signaling, which is largely executed by the phosphoinositol 3-kinase (PI3K)-like kinases ATM, ATR, and DNA-dependent protein kinase (DNA-PK), the checkpoint kinases Chk1 and Chk2, and members of the mitogen-activated protein kinase (MAPK) family (3, 4), protein modifications by ubiquitin and ubiquitin-like moieties are crucial at all levels of the DDR (5).The ubiquitination machinery can form various, differentially interpreted tags, including both degradative (K48-and K11-linked chains) and nondegradative (monoubiquitination and K63-linked chains) signals (6). Furthermore, a growing family of ubiquitin-like modifications, such as SUMO, Nedd8, and ISG15, has been identified, mostly providing nondegradative signals. Multiple enzymes are shared between the ubiquitinat...

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“…In mammals, the Atg8 homolog LC3BI is conjugated with phosphatidylethanolamine, forming LC3BII and resulting in the maturation of autophagosomes, which associate with lysosomes to form autophagolysosomes [3] . When cells suffer extra-or intracellular stress, the level of autophagy could be remarkably activated as a cytoprotective response, resulting in adaptation and survival [4,5] , while autophagic cell death could occur with dysregulated or excessive autophagy.…”

Section: Introductionmentioning

confidence: 99%

Retigeric acid B-induced mitophagy by oxidative stress attenuates cell death against prostate cancer cells in vitro

Liu

et al. 2013

Acta Pharmacol Sin

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Aim: Retigeric acid B (RAB), a pentacyclic triterpenic acid from Lobaria kurokawae Yoshim, has been found to induce apoptosis in prostate cancer cells. The aim of this study was to investigate the roles of mitochondrial damage-caused mitophagy in RAB-induced prostate cancer cell death in vitro. Methods: Human prostate cancer PC3 and LNCaP cells were tested. Cell viability was analyzed with MTT assay. Cell apoptosis, ROS level and mitochondrial transmembrane potential (mtΔψ) were measured with flow cytometry. Autophagy-and apoptosis-related proteins were studied using Western blotting. GFP-LC3B puncta, mitochondrial swelling and mitophagy were examined morphologically. Quantitative RT-PCR was used to measure LC3B mRNA level, and siRNA was used to knock down LC3BII. Results: In both PC3 and LNCaP cells, RAB (15 µmol/L) increased ROS accumulation and decreased mtΔψ in a time-dependent manner. Furthermore, RAB induced mitochondrial swelling and mitophagy, significantly increased LC3B expression and conversion of LC3BI to LC3BII, and the elimination of mitochondria by LC3BII-containing autophagolysosomes. In addition, RAB suppressed the PI3K/Akt/mTOR pathway activation. Pretreatment of PC3 cells with autophagy inhibitor 3-MA (5 mmol/L) or the lysosomal protease inhibitor CQ (10 µmol/L) significantly increased RAB-induced apoptosis. Similar results were obtained in RAB-treated PC3 cells with LC3B knocked down. Conclusion: RAB induces mitochondrial damage and mitophagy that attenuates RAB-induced prostate cancer cell death. Thus, suppression of mitophagy might be a potential strategy for improving the chemotherapeutic effects of RAB.

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Endoplasmic Reticulum Stress, the Unfolded Protein Response, Autophagy, and the Integrated Regulation of Breast Cancer Cell Fate

Cited by 189 publications

References 126 publications

Polyploidization of Murine Mesenchymal Cells Is Associated with Suppression of the Long Noncoding RNA H19 and Reduced Tumorigenicity

Polyploidization of Murine Mesenchymal Cells Is Associated with Suppression of the Long Noncoding RNA H19 and Reduced Tumorigenicity

The E3 Ubiquitin Ligase ARIH1 Protects against Genotoxic Stress by Initiating a 4EHP-Mediated mRNA Translation Arrest

Retigeric acid B-induced mitophagy by oxidative stress attenuates cell death against prostate cancer cells in vitro

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