TRB3 reverses chemotherapy resistance and mediates crosstalk between endoplasmic reticulum stress and AKT signaling pathways in MHCC97H human hepatocellular carcinoma cells

Yang, Li; Zhu, Da‐Yuan; Hou, Lidan; Xu, Min; Meng, Xiangjun

doi:10.3892/ol.2017.7361

Cited by 12 publications

(13 citation statements)

References 22 publications

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“…For RNA-seq data for the TMZ-sensitive LN229 cells ( Figure 5 ), when comparing combined TMZ + OKN to UT treatments ( Figure 5 A ), an interesting downregulated gene includes PODXL (a marker for gastric cancer [53] ), and interesting upregulated genes include TRIB3 (induces apoptosis and reverses resistance to chemotherapy in hepatic carcinoma cells [54] ) and CHAC1 (enhances glioma apoptosis [55] ). When comparing combined TMZ + OKN treatment to TMZ alone ( Figure 5 B ), interesting downregulated genes are IGR1 (associated with shorter disease-free survival in patients whose tumors are ER positive and HER2 positive [56] ; IGF1R signaling pathway is very relevant in drug resistance [57] ), XIST (increased level associated with shorter survival and poorer prognosis [58] ), and PRKDC (prognostic biomarker for chemoresistance in breast cancer patients [59] ).…”

Section: Discussionmentioning

confidence: 99%

OKN-007 Increases temozolomide (TMZ) Sensitivity and Suppresses TMZ-Resistant Glioblastoma (GBM) Tumor Growth

Towner

Smith

Saunders

et al. 2019

Translational Oncology

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Treatment of glioblastoma (GBM) remains a challenge using conventional chemotherapy, such as temozolomide (TMZ), and is often ineffective as a result of drug resistance. We have assessed a novel nitrone-based agent, OKN-007, and found it to be effective in decreasing tumor volumes and increasing survival in orthotopic GBM xenografts by decreasing cell proliferation and angiogenesis and increasing apoptosis. In this study, we assessed combining OKN-007 with TMZ in vivo in a human G55 GBM orthotopic xenograft model and in vitro in TMZ-resistant and TMZ-sensitive human GBM cell lines. For the in vivo studies, magnetic resonance imaging was used to assess tumor growth and vascular alterations. Percent animal survival was also determined. For the in vitro studies, cell growth, IC50 values, RNA-seq, RT-PCR, and ELISA were used to assess growth inhibition, possible mechanism-of actions (MOAs) associated with combined OKN-007 + TMZ versus TMZ alone, and gene and protein expression levels, respectively. Microarray analysis of OKN-007–treated rat F98 glioma tumors was also carried out to determine possible MOAs of OKN-007 in glioma-bearing animals either treated or not treated with OKN-007. OKN-007 seems to elicit its effect on GBM tumors via inhibition of tumorigenic TGF-β1, which affects the extracellular matrix. When combined with TMZ, OKN-007 significantly increases percent survival, decreases tumor volumes, and normalizes tumor blood vasculature in vivo compared to untreated tumors and seems to affect TMZ-resistant GBM cells possibly via IDO-1, SUMO2, and PFN1 in vitro. Combined OKN-007 + TMZ may be a potentially potent treatment strategy for GBM patients.

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Section: Discussionmentioning

confidence: 99%

OKN-007 Increases temozolomide (TMZ) Sensitivity and Suppresses TMZ-Resistant Glioblastoma (GBM) Tumor Growth

Towner

Smith

Saunders

et al. 2019

Translational Oncology

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“…The binding site of CHOP overlaps the amino acid response elements in the TRB3 promoter, and the specific regions in CHOP and TRB3 are responsible for their interaction (69). The expression of TRB3 can inhibit AKT activity and has a pro-apoptotic capacity (70, 71). AKT directly modulates the expression of caspase-3 and caspase-9, as well as the mitochondrial pro-apoptotic proteins, BAX, and BAD (72).…”

Section: The Functions Of Chop In Er Stress-induced Apoptosismentioning

confidence: 99%

The C/EBP Homologous Protein (CHOP) Transcription Factor Functions in Endoplasmic Reticulum Stress-Induced Apoptosis and Microbial Infection

et al. 2019

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Apoptosis is a form of cell death by which the body maintains the homeostasis of the internal environment. Apoptosis is an initiative cell death process that is controlled by genes and is mainly divided into endogenous pathways (mitochondrial pathway), exogenous pathways (death receptor pathway), and apoptotic pathways induced by endoplasmic reticulum (ER) stress. The homeostasis imbalance in ER results in ER stress. Under specific conditions, ER stress can be beneficial to the body; however, if ER protein homeostasis is not restored, the prolonged activation of the unfolded protein response may initiate apoptotic cell death via the up-regulation of the C/EBP homologous protein (CHOP). CHOP plays an important role in ER stress-induced apoptosis and this review focuses on its multifunctional roles in that process, as well as its role in apoptosis during microbial infection. We summarize the upstream and downstream pathways of CHOP in ER stress induced apoptosis. We also focus on the newest discoveries in the functions of CHOP-induced apoptosis during microbial infection, including DNA and RNA viruses and some species of bacteria. Understanding how CHOP functions during microbial infection will assist with the development of antimicrobial therapies.

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“…The phosphorylation of eIF2α not only inhibits protein translation but also upregulates the expression of activating transcription factor 4 (ATF4) ( Avril et al, 2017 ). ATF4 activates C/EBP homologous protein (CHOP) ( Li Y. et al, 2018 ). It has been reported ( Wang et al, 2017 ; B'Chir et al, 2014 ) that the activation of CHOP via ERS can induce autophagy or apoptosis.…”

Section: Intrinsic Drug-induced Ers and Drug Resistance In Solid Tumorsmentioning

confidence: 99%

The Road of Solid Tumor Survival: From Drug-Induced Endoplasmic Reticulum Stress to Drug Resistance

Cao

Tang

Huang

et al. 2021

Front. Mol. Biosci.

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Endoplasmic reticulum stress (ERS), which refers to a series of adaptive responses to the disruption of endoplasmic reticulum (ER) homeostasis, occurs when cells are treated by drugs or undergo microenvironmental changes that cause the accumulation of unfolded/misfolded proteins. ERS is one of the key responses during the drug treatment of solid tumors. Drugs induce ERS by reactive oxygen species (ROS) accumulation and Ca2+ overload. The unfolded protein response (UPR) is one of ERS. Studies have indicated that the mechanism of ERS-mediated drug resistance is primarily associated with UPR, which has three main sensors (PERK, IRE1α, and ATF6). ERS-mediated drug resistance in solid tumor cells is both intrinsic and extrinsic. Intrinsic ERS in the solid tumor cells, the signal pathway of UPR-mediated drug resistance, includes apoptosis inhibition signal pathway, protective autophagy signal pathway, ABC transporter signal pathway, Wnt/β-Catenin signal pathway, and noncoding RNA. Among them, apoptosis inhibition is one of the major causes of drug resistance. Drugs activate ERS and its downstream antiapoptotic proteins, which leads to drug resistance. Protective autophagy promotes the survival of solid tumor cells by devouring the damaged organelles and other materials and providing new energy for the cells. ERS induces protective autophagy by promoting the expression of autophagy-related genes, such as Beclin-1 and ATG5–ATG12. ABC transporters pump drugs out of the cell, which reduces the drug-induced apoptosis effect and leads to drug resistance. In addition, the Wnt/β-catenin signal pathway is also involved in the drug resistance of solid tumor cells. Furthermore, noncoding RNA regulates the ERS-mediated survival and death of solid tumor cells. Extrinsic ERS in the solid tumor cells, such as ERS in immune cells of the tumor microenvironment (TME), also plays a crucial role in drug resistance by triggering immunosuppression. In immune system cells, ERS in dendritic cells (DCs) and myeloid-derived suppressor cells (MDSCs) influences the antitumor function of normal T cells, which results in immunosuppression. Meanwhile, ERS in T cells can also cause impaired functioning and apoptosis, leading to immunosuppression. In this review, we highlight the core molecular mechanism of drug-induced ERS involved in drug resistance, thereby providing a new strategy for solid tumor treatment.

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TRB3 reverses chemotherapy resistance and mediates crosstalk between endoplasmic reticulum stress and AKT signaling pathways in MHCC97H human hepatocellular carcinoma cells

Cited by 12 publications

References 22 publications

OKN-007 Increases temozolomide (TMZ) Sensitivity and Suppresses TMZ-Resistant Glioblastoma (GBM) Tumor Growth

OKN-007 Increases temozolomide (TMZ) Sensitivity and Suppresses TMZ-Resistant Glioblastoma (GBM) Tumor Growth

The C/EBP Homologous Protein (CHOP) Transcription Factor Functions in Endoplasmic Reticulum Stress-Induced Apoptosis and Microbial Infection

The Road of Solid Tumor Survival: From Drug-Induced Endoplasmic Reticulum Stress to Drug Resistance

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