RACK1 modulates apoptosis induced by sorafenib in HCC cells by interfering with the IRE1/XBP1 axis

Zhou, Ti; Lv, Xing; Guo, Xin; Ruan, Bai; Liu, Dong; Ding, Rui; Gao, Yuan; Ding, Jie; Dou, Kefeng; Chen, Yong

doi:10.3892/or.2015.3920

Cited by 32 publications

(25 citation statements)

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“…Based on these findings, inhibition of IRE1α/XBP1 was proposed as a possible strategy for PCa treatment. In another study, interaction between IRE1α and RACK1 was crucial for the activation of IRE1α/XBP1 signalling upon unfolded protein response induced by sorafenib in hepatocellular carcinoma cells [ 51 ], further supporting the interconnection between MYC signalling and ER processes.…”

Section: Discussionmentioning

confidence: 88%

Molecular Changes in Tissue Proteome during Prostate Cancer Development: Proof-of-Principle Investigation

et al. 2020

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(1) Background: Prostate cancer (PCa) is characterized by high heterogeneity. The aim of this study was to investigate molecular alterations underlying PCa development based on proteomics data. (2) Methods: Liquid chromatography coupled to tandem mass spectrometry was conducted for 22 fresh-frozen tissue specimens from patients with benign prostatic hyperplasia (BPH, n = 5) and PCa (n = 17). Mann Whitney test was used to define significant differences between the two groups. Association of protein abundance with PCa progression was evaluated using Spearman correlation, followed by verification through investigating the Prostate Cancer Transcriptome Atlas. Functional enrichment and interactome analysis were carried out using Metascape and String. (3) Results: Proteomics analysis identified 1433 proteins, including 145 proteins as differentially abundant between patients with PCa and BPH. In silico analysis revealed alterations in several pathways and hallmarks implicated in metabolism and signalling, represented by 67 proteins. Among the latter, 21 proteins were correlated with PCa progression at both the protein and mRNA levels. Interactome analysis of these 21 proteins predicted interactions between Myc proto-oncogene (MYC) targets, protein processing in the endoplasmic reticulum, and oxidative phosphorylation, with MYC targets having a central role. (4) Conclusions: Tissue proteomics allowed for characterization of proteins and pathways consistently affected during PCa development. Further validation of these findings is required.

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Section: Discussionmentioning

confidence: 88%

Molecular Changes in Tissue Proteome during Prostate Cancer Development: Proof-of-Principle Investigation

et al. 2020

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“… 48 , 53 , 57 , 59 , 61 , 65 , 67 In experimental models including tumor cell lines and mouse tumor xenografts, GRP78 was also shown to have an important role in regulating cancer hallmarks ( Table 2 ). 46 , 47 , 48 , 51 , 54 , 55 , 56 , 57 , 59 , 60 , 61 , 65 , 66 , 68 , 69 , 70 , 71 , 72 , 73 For example, GRP78 regulates tumor cell proliferation and migration. 47 , 59 , 65…”

Section: Upr Molecular Mechanisms and Their Functions In Cancers: Thementioning

confidence: 99%

“…Correlations between UPR activation and chemotherapy resistance were mainly demonstrated in cellular models in many types of cancer ( Table 5 ). 46 , 47 , 48 , 51 , 52 , 53 , 54 , 57 , 60 , 62 , 64 , 71 , 72 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 A vast number of these studies demonstrate the impact of GRP78 expression on drug resistance mainly involving a reduced effect of drug-induced apoptosis. 47 , 48 , 54 , 60 , 64 , 116 , 117 , 120 , 123 , 125 , 128 , 129 However, the precise molecular mechanisms involved remain to be discovered.…”

Section: Chemotherapy Resistance Induced By Uprmentioning

confidence: 99%

Endoplasmic reticulum stress signaling and chemotherapy resistance in solid cancers

2017

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The unfolded protein response (UPR) is an adaptive cellular program used by eukaryotic cells to cope with protein misfolding stress. During tumor development, cancer cells are facing intrinsic (oncogene activation) and extrinsic (limiting nutrient or oxygen supply) challenges, with which they must cope to survive. Moreover, chemotherapy represents an additional extrinsic challenge that cancer cells are facing and to which they adapt in the case of resistance. As of today, resistance to chemotherapy and targeted therapies is one of the important issues that oncologists have to deal with for treating cancer patients. In this review, we first describe the key molecular mechanisms controlling the UPR and their implication in solid cancers. Then, we review the literature that connects cancer chemotherapy resistance mechanisms and activation of the UPR. Finally, we discuss the possible applications of targeting the UPR to bypass drug resistance.

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“…One of the www.nature.com/scientificreports/ possible explanations for this is the differences in the time course of these experiments. The expression levels of the markers were measured after 24-h treatment with the candidate compounds to maximize detection sensitivity, while evaluation of XBP1 splicing was performed after a 6-h treatment [20][21][22] . This short treatment duration is suitable for the evaluation and description of the effects of a drug because longer-term treatment can result in feedback reactions and blunt the effects of interest.…”

Section: Discussionmentioning

confidence: 99%

Decomposition profile data analysis of multiple drug effects identifies endoplasmic reticulum stress-inducing ability as an unrecognized factor

Morita

Mizuno

Kusuhara

2020

Sci Rep

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Chemicals have multiple effects in biological systems. Because their on-target effects dominate the output, their off-target effects are often overlooked and can sometimes cause dangerous adverse events. Recently, we developed a novel decomposition profile data analysis method, orthogonal linear separation analysis (OLSA), to analyse multiple effects. In this study, we tested whether OLSA identified the ability of drugs to induce endoplasmic reticulum (ER) stress as a previously unrecognized factor. After analysing the transcriptome profiles of MCF7 cells treated with different chemicals, we focused on a vector characterized by well-known ER stress inducers, such as ciclosporin A. We selected five drugs predicted to be unrecognized ER stress inducers, based on their inducing ability scores derived from OLSA. These drugs actually induced X-box binding protein 1 splicing, an indicator of ER stress, in MCF7 cells in a concentration-dependent manner. Two structurally different representatives of the five test compounds exhibited similar results in HepG2 and HuH7 cells, but not in PXB primary hepatocytes derived from human-liver chimeric mice. These results indicate that our decomposition strategy using OLSA uncovered the ER stress-inducing ability of drugs as an unrecognized effect, the manifestation of which depended on the background of the cells. Small compounds have the capacity to interact with multiple cellular proteins, thereby mediating multiple effects depending on their exposure to interacting proteins. It is quite difficult to identify the full range of effects of a new chemical, even for its developers, and some factors may be unrecognized. Even approved drugs show off-target effects that are often unrecognized during drug development, and which can lead to adverse reactions including lethal effects. For instance, astemizole has been withdrawn from the market in most countries because it causes a fatal side effect, cardiac arrhythmia 1,2 , by blocking the human Ether-ago go Related Gene potassium channel, thereby causing QT interval prolongation and torsade de pointes. However, we should not be too negative about unrecognized effects of small compounds, because identification of these can lead to drug repurposing. For example, memantine was synthesized in 1968 as a derivative of amantadine, an anti-influenza agent. Recently, it was revealed that this anti-influenza agent is also an antagonist for the N-methyl-D-aspartate receptor, and the drug has become a medication for dementia 3. Thus, the important question is how such unrecognized effects of chemicals can be identified. Profile data analysis is quite useful in addressing this issue. Although the terminology sometimes varies between contexts, the method is a type of multivariate analysis that describes data using multiple variables and investigates the relationship between data with high robustness and detection power by sharing information about the structure of the data 4. Data from "omics" analysis, which converts biological information of a specim...

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RACK1 modulates apoptosis induced by sorafenib in HCC cells by interfering with the IRE1/XBP1 axis

Cited by 32 publications

References 33 publications

Molecular Changes in Tissue Proteome during Prostate Cancer Development: Proof-of-Principle Investigation

Molecular Changes in Tissue Proteome during Prostate Cancer Development: Proof-of-Principle Investigation

Endoplasmic reticulum stress signaling and chemotherapy resistance in solid cancers

Decomposition profile data analysis of multiple drug effects identifies endoplasmic reticulum stress-inducing ability as an unrecognized factor

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