Cross-talk between Endoplasmic Reticulum (ER) Stress and the MEK/ERK Pathway Potentiates Apoptosis in Human Triple Negative Breast Carcinoma Cells

Ghosh, Swatilekha; Adhikary, Arghya; Chakraborty, Supriya; Bhattacharjee, Pushpak; Mazumder, Minakshi; Putatunda, Salil; Gorain, Mahadeo; Chakraborty, Arijit; Kundu, Gopal C.; Das, Tanya; Sen, Parimal C.

doi:10.1074/jbc.m114.594028

Cited by 27 publications

(19 citation statements)

References 42 publications

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“…It has been identified that upregulation of ER stress may induce apoptosis of cancer cells ( 41 , 42 ). ER stress upregulation potentiating apoptosis also has been observed in human triple negative breast carcinoma cells ( 43 ). In the present study, it has been demonstrated that ATF6, IER1 RERK, and CHOP expression levels were increased by synergetic treatment of I-131 and LEB in NPC cells and tumor tissues.…”

Section: Discussionmentioning

confidence: 84%

Combined effects of Lenvatinib and iodine‑131 on cell apoptosis in nasopharyngeal carcinoma through inducing endoplasmic reticulum stress

Wang

Zhuang

et al. 2018

Exp Ther Med

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Nasopharyngeal carcinoma (NPC) is a type of malignant tumor characterized by high invasiveness, metastatic potential and worldwide incidence among patients with head and neck cancer. It has previously been demonstrated that Lenvatinib (LEB) is an efficient anti-cancer agent by multi-targeting of tyrosine kinase inhibitors. Iodine-131 (I-131) therapy has been accepted for the treatment of thyroid cancer and other carcinomas. In the present study, the combined effects of LEB and I-131 were investigated on NPC and the potential signal pathway mediated by LEB and I-131 on NPC cells was explored. Inhibitory effects of LEB and I-131 for NPC cells growth were investigated via MTT assay. Migration and invasion of NPC cells was studied by aggression assays following incubation of LEB and I-131. Apoptosis of NPC cells and tissues were analyzed via flow cytometry and TUNEL assay, respectively. Apoptosis-related gene expression levels in NPC cells following treatment with LEB and I-131 were determined by western blotting. Endoplasmic reticulum (ER) stress in NPC cells were analyzed in NPC cells and tumor tissues. Immunohistochemistry was used to analyze the efficacy of LEB and I-131 in NPC-tumor bearing mice. The results demonstrated that combined treatment of LEB and I-131 significantly inhibited growth, apoptosis, migration and invasion of NPC cells compared with single agent therapy. Apoptosis-related gene expression levels of caspase-3 and caspase-9 were upregulated by LEB and I-131, whereas B call lymphoma-2, and P53 were downregulated in NPC cells and tumor tissues. In addition, signal mechanism analysis demonstrated that combined treatment of LEB and I-131 promoted expression levels of activating transcription factor 6, inositol-requiring protein 1 (IER1), protein kinase RNA-like endoplasmic reticulum kinase (RERK), and C/EBP homologous protein in NPC cells. Furthermore, combined treatment of LEB and I-131 markedly inhibited in vivo growth of NPC and further prolonged survival of experimental mice compared with single agent and control groups. Immunohistochemistry indicated that c-jun N-terminal kinase and Caspase-3 were increased in NPS tumor tissues in xenograft models treated with LEB and I-131. Apoptotic bodies were also increased in tumors treated by LEB and I-131. In conclusion, these findings indicate that combined treatment of LEB and I-131 may inhibit NPC growth and aggression through upregulation of ER stress, suggesting combined treatment of LEB and I-131 may be a potential therapeutic schedule for the treatment of NPC.

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Section: Discussionmentioning

confidence: 84%

Combined effects of Lenvatinib and iodine‑131 on cell apoptosis in nasopharyngeal carcinoma through inducing endoplasmic reticulum stress

Wang

Zhuang

et al. 2018

Exp Ther Med

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“…In contrast, the Erk1/2 (p42/44) kinases were induced only at moderate doses of Tm, with peak activation being observed at 20-50 nM. Erk1/2 signaling has been associated with ER stress in prior studies and in some cases has been shown to serve a pro-survival or autophagyinducing role in the cellular response (Arai et al 2004;Jiang et al 2007;Ghosh et al 2015). Inhibition of the MEK/ERK pathway was recently shown to dramatically increase apoptosis activation in breast cancer cells experiencing ER stress (Ghosh et al 2015).…”

Section: Discussionmentioning

confidence: 99%

“…Erk1/2 signaling has been associated with ER stress in prior studies and in some cases has been shown to serve a pro-survival or autophagyinducing role in the cellular response (Arai et al 2004;Jiang et al 2007;Ghosh et al 2015). Inhibition of the MEK/ERK pathway was recently shown to dramatically increase apoptosis activation in breast cancer cells experiencing ER stress (Ghosh et al 2015). The restriction of Erk1/2 signaling to lower doses of Tm in our study may identify an important protective measure induced by cells during adaptation to survivable levels of ER dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Moderate endoplasmic reticulum stress activates a PERK and p38-dependent apoptosis

Lumley

Osborn

Scott

et al. 2017

Cell Stress and Chaperones

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The endoplasmic reticulum (ER) has the ability to signal organelle dysfunction via a complex signaling network known as the unfolded protein response (UPR). In this work, hamster fibroblast cells exhibiting moderate levels of ER stress were compared to those exhibiting severe ER stress. Inhibition of N-linked glycosylation was accomplished via a temperature-sensitive mutation in the Dad1 subunit of the oligosaccharyltransferase (OST) complex or by direct inhibition with tunicamycin (Tm). Temperature shift (TS) treatment generated weak activation of ER stress signaling when compared to doses of Tm that are typically used in ER stress studies (500-1000 nM). A dose-response analysis of key ER stress signaling mediators, inositol-requiring enzyme 1 (IRE1) and protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), revealed 20-40 nM of Tm to generate activation intensity similar to TS treatment. In parental BHK21 cells, moderate (20-40 nM) and high doses (200-1000 nM) of Tm were compared to identify physiological and signaling-based differences in stress response. Inhibition of ER Ca release via ITPR activity with 2-aminoethoxydiphenyl borate (2-APB) or Xestospongin C (XeC) was sufficient to protect against apoptosis induced by moderate but not higher doses of Tm. Analysis of kinase activation over a range of Tm exposures revealed the p38 stress-activated protein kinase (SAPK) to display increasing activation with Tm dosage. Interestingly, Tm induced the extracellular regulated kinases (Erk1/2) only at moderate doses of Tm. Inhibition of ER transmembrane stress sensors (IRE1, PERK) or cytosolic signaling mediators (p38, Jnk1, Erk1/2) was used to evaluate pathways involved in apoptosis activation during ER stress. Inhibition of either PERK or p38 was sufficient to reduce cell death and apoptosis induced by moderate, but not high, doses of Tm. During ER stress, cells exhibited a rapid decline in anti-apoptotic Mcl-1 and survivin proteins. Inhibition of PERK was sufficient to block this affect. This work reveals moderate doses of ER stress to generate patterns of stress signaling that are distinct from higher doses and that apoptosis activation at moderate levels of stress are dependent upon PERK and p38 signaling. Studies exploring ER stress signaling should recognize that this signaling acts as a rheostat rather than a simple switch, behaving distinctively in a dose-dependent manner.

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“…This suggests that TNBC cells may be more vulnerable to CHOP activation than cells that are not known for the XBP1 activation (such as estrogen receptor positive adenocarcinoma cell line MCF7). 22, 23 To test this idea, we compared the viabilities of HCC-1086 cells and MCF7 cells treated with 3d . As shown in Figure 3D, treatment of 3d caused the death in both cell lines in a dose-dependent manner.…”

Section: Resultsmentioning

confidence: 99%

Identification of 5-nitrofuran-2-amide derivatives that induce apoptosis in triple negative breast cancer cells by activating C/EBP-homologous protein expression

Duan

Liu

Lim

et al. 2015

Bioorganic & Medicinal Chemistry

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The transcription factor C/EBP-homologous protein (CHOP) is a key component of the terminal unfolded protein response (UPR) that mediates unresolvable endoplasmic reticulum stress-induced apoptosis. CHOP induction is known to cause cancer cell death. Chemicals that induce CHOP expression would thus be valuable as potential cancer therapeutics and as research tools. Here, we identified 5-nitrofuran-2-amide derivatives as small molecule activators of CHOP expression that induced apoptosis in triple negative breast cancer (TNBC) cells. Our preliminary structure-activity relationship studies indicated that compounds with an N-phenyl-5-nitrofuran-2-carboxamide skeleton were particularly potent inducers of TNBC cell apoptosis. The compounds activate CHOP expression via the PERK–eIF2α–ATF4 branch of the UPR. These results indicate that small molecule activators of CHOP expression may have therapeutic potential for TNBC.

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Cross-talk between Endoplasmic Reticulum (ER) Stress and the MEK/ERK Pathway Potentiates Apoptosis in Human Triple Negative Breast Carcinoma Cells

Cited by 27 publications

References 42 publications

Combined effects of Lenvatinib and iodine‑131 on cell apoptosis in nasopharyngeal carcinoma through inducing endoplasmic reticulum stress

Combined effects of Lenvatinib and iodine‑131 on cell apoptosis in nasopharyngeal carcinoma through inducing endoplasmic reticulum stress

Moderate endoplasmic reticulum stress activates a PERK and p38-dependent apoptosis

Identification of 5-nitrofuran-2-amide derivatives that induce apoptosis in triple negative breast cancer cells by activating C/EBP-homologous protein expression

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