Sustained IRE1 and ATF6 signaling is important for survival of melanoma cells undergoing ER stress

Tay, Kwang Hong; Luan, Qi; Croft, Amanda; Jiang, Chen Chen; Jin, Lei; Zhang, Xu Dong; Tseng, Hsin‐Yi

doi:10.1016/j.cellsig.2013.11.008

Cited by 80 publications

(55 citation statements)

References 38 publications

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“…[8][9][10][11] The UPR is essentially a cellular protective response, but excessive or prolonged UPR can kill cells primarily by induction of apoptosis. [12][13][14] Of note, previous studies have shown that many types of cancer cells including melanoma cells are relatively resistant to apoptosis triggered by pharmacological ER stress inducers such as tunicamycin (TM) and thapsigargin (TG). 15,16 A number of mechanisms, such as upregulation of the prosurvival BCL2 family protein MCL1 and activation of the mitogen-activated protein kinase kinase 1 (MAP2K1)-MAPK1/3 and phosphoinositide 3-kinase (PI3K)-AKT signaling pathways contribute to reduced susceptibility of melanoma cells to pharmacological ER stress-induced cell death.…”

Section: Ripk1 (Receptor [Tnfrsf]mentioning

confidence: 99%

“…83 Short hairpin RNA (shRNA) knockdown Sigma-Aldrich MISSION Ò Lentiviral Transduction Particles for shRNA-mediated knockdown of ERN1 (SHCLNV-NM_001433), ATF6 (SHCLNV-NM_007348) and EIF2AK3 (SHCLNV-NM_032025) were purchased from Sigma-Aldrich and used as described previously. 14 The human RIPK1 shRNA (TG320591), BCL2L11 shRNA (TG306422), BECN1 shRNA (TG314484) and scrambled shRNA (TG300130), were purchased from Origene, and were used to infect cells according to the manufacturer's protocol.…”

Section: Small Interference Rnamentioning

confidence: 99%

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RIPK1 regulates survival of human melanoma cells upon endoplasmic reticulum stress through autophagy

et al. 2015

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(2015) RIPK1 regulates survival of human melanoma cells upon endoplasmic reticulum stress through autophagy, Autophagy, 11:7, 975-994, DOI: 10.1080/15548627.2015 Keywords: autophagy, cell death, endoplasmic reticulum stress, melanoma, RIPK1Abbreviations: 3-MA, 3-methyladenine; AMPK, AMP-activated protein kinase; ATF6, activating transcription factor 6; Baf A1, bafilomycin A 1 ; CAMKK2, calcium/calmodulin-dependent protein kinase kinase 2: b; EIF2AK3/PERK, eukaryotic translation initiation factor 2-a kinase 3; ER, endoplasmic reticulum; ERN1/IRE1, endoplasmic reticulum to nucleus signaling 1; HSF1, heat shock transcription factor 1; HSPA5, heat shock 70kDa protein 5 (glucose-regulated protein: 78kDa); MAP2K1/MEK1, mitogenactivated protein kinase kinase 1; MAPK, mitogen-activated protein kinase; MAPK1/ERK2, mitogen-activated protein kinase 1; MAPK3/ERK1, mitogen-activated protein kinase 3; MAPK8/JNK1, mitogen-activated protein kinase 8; MAPK9/JNK2, mitogenactivated protein kinase 9; MAPK11/p38b, mitogen-activated protein kinase 11; MAPK12/p38g, mitogen-activated protein kinase 12; MAPK13/p38d, mitogen-activated protein kinase 13; MAPK14/p38a, mitogen-activated protein kinase 14; NFKB1, nuclear factor of kappa light polypeptide gene enhancer in B-cells 1; PRKAA1, protein kinase AMP-activated: a 1 catalytic subunit; RIPK1, receptor (TNFRSF)-interacting protein kinase 1; SQSTM1/p62, sequestosome 1; TG, thapsigargin; TM, tunicamycin; TNFRSF1A/ TNFR1, tumor necrosis factor receptor superfamily: member 1A; UPR, unfolded protein response; XBP1, x-box binding protein 1.Although RIPK1 (receptor [TNFRSF]-interacting protein kinase 1) is emerging as a critical determinant of cell fate in response to cellular stress resulting from activation of death receptors and DNA damage, its potential role in cell response to endoplasmic reticulum (ER) stress remains undefined. Here we report that RIPK1 functions as an important prosurvival mechanism in melanoma cells undergoing pharmacological ER stress induced by tunicamycin (TM) or thapsigargin (TG) through activation of autophagy. While treatment with TM or TG upregulated RIPK1 and triggered autophagy in melanoma cells, knockdown of RIPK1 inhibited autophagy and rendered the cells sensitive to killing by TM or TG, recapitulating the effect of inhibition of autophagy. Consistently, overexpression of RIPK1 enhanced induction of autophagy and conferred resistance of melanoma cells to TM-or TG-induced cell death. Activation of MAPK8/JNK1 or MAPK9/JNK2, which phosphorylated BCL2L11/BIM leading to its dissociation from BECN1/Beclin 1, was involved in TM-or TG-induced, RIPK1-mediated activation of autophagy; whereas, activation of the transcription factor HSF1 (heat shock factor protein 1) downstream of the ERN1/IRE1-XBP1 axis of the unfolded protein response was responsible for the increase in RIPK1 in melanoma cells undergoing pharmacological ER stress. Collectively, these results identify upregulation of RIPK1 as an important resistance mechanism of melanoma cells to TM-or TG-induced ...

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Section: Ripk1 (Receptor [Tnfrsf]mentioning

confidence: 99%

Section: Small Interference Rnamentioning

confidence: 99%

RIPK1 regulates survival of human melanoma cells upon endoplasmic reticulum stress through autophagy

et al. 2015

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“…In this study, we found that NELL2 increased expression of sXBP1 and ER chaperones, such as GRP94, BiP, and calnexin. A recent study suggested that ERK signaling is required for activation of IRE1 and ATF6 pathways and sXBP1 in melanoma cells undergoing ER stress and is important for attenuation of ER stress (Tay et al, 2014). Therefore, NELL2 may regulate sXBP1 and BiP through the ERK signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

NELL2 Function in the Protection of Cells against Endoplasmic Reticulum Stress

Kim

et al. 2015

Molecules and Cells

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* Continuous intra-and extracellular stresses induce disorder of Ca2+ homeostasis and accumulation of unfolded protein in the endoplasmic reticulum (ER), which results in ER stress. Severe long-term ER stress triggers apoptosis signaling pathways, resulting in cell death. Neural epidermal growth factor-like like protein 2 (NELL2) has been reported to be important in protection of cells from cell death-inducing environments. In this study, we investigated the cytoprotective effect of NELL2 in the context of ER stress induced by thapsigargin, a strong ER stress inducer, in Cos7 cells. Overexpression of NELL2 prevented ER stress-mediated apoptosis by decreasing expression of ER stress-induced C/EBP homologous protein (CHOP) and increasing ER chaperones. In this context, expression of anti-apoptotic Bcl-xL was increased by NELL2, whereas NELL2 decreased expression of pro-apoptotic proteins, such as cleaved caspases 3 and 7. This antiapoptotic effect of NELL2 is likely mediated by extracellular signal-regulated kinase (ERK) signaling, because its inhibitor, U0126, inhibited effects of NELL2 on the expression of anti-and pro-apoptotic proteins and on the protection from ER stress-induced cell death.

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“…Although these 3 ER transmembrane stress sensors are often activated at the same time on ER stress, recent studies have revealed that some of these sensors are specifically activated depending on the stimuli involved. 25,26 On ER stress, ATF6 is cleaved, and the cleaved ATF6 can act as a transcription factor to induce the expression of downstream genes that protect the heart from ischemia/reperfusion injury and hypertrophy. 16 In the present study, however, we found that doxorubicin suppressed the expression of genes downstream of ATF6, although it induced ATF6 cleavage in cardiomyocytes ( Figures 1C and 2B).…”

Section: Doxorubicin Can Cause Er Dilation and Er Stressmentioning

confidence: 99%

Chemical Endoplasmic Reticulum Chaperone Alleviates Doxorubicin-Induced Cardiac Dysfunction

Shoji

Matsuzaki

et al. 2016

Circulation Research

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Rationale: Doxorubicin is an effective chemotherapeutic agent for cancer, but its use is often limited by cardiotoxicity. Doxorubicin causes endoplasmic reticulum (ER) dilation in cardiomyocytes, and we have demonstrated that ER stress plays important roles in the pathophysiology of heart failure. Objective: We evaluated the role of ER stress in doxorubicin-induced cardiotoxicity and examined whether the chemical ER chaperone could prevent doxorubicin-induced cardiac dysfunction. Methods and Results: We confirmed that doxorubicin caused ER dilation in mouse hearts, indicating that doxorubicin may affect ER function. Doxorubicin activated an ER transmembrane stress sensor, activating transcription factor 6, in cultured cardiomyocytes and mouse hearts. However, doxorubicin suppressed the expression of genes downstream of activating transcription factor 6, including X-box binding protein 1. The decreased levels of X-box binding protein 1 resulted in a failure to induce the expression of the ER chaperone glucose-regulated protein 78 which plays a major role in adaptive responses to ER stress. In addition, doxorubicin activated caspase-12, an ER membrane–resident apoptotic molecule, which can lead to cardiomyocyte apoptosis and cardiac dysfunction. Cardiac-specific overexpression of glucose-regulated protein 78 by adeno-associated virus 9 or the administration of the chemical ER chaperone 4-phenylbutyrate attenuated caspase-12 cleavage, and alleviated cardiac apoptosis and dysfunction induced by doxorubicin. Conclusions: Doxorubicin activated the ER stress–initiated apoptotic response without inducing the ER chaperone glucose-regulated protein 78, further augmenting ER stress in mouse hearts. Cardiac-specific overexpression of glucose-regulated protein 78 or the administration of the chemical ER chaperone alleviated the cardiac dysfunction induced by doxorubicin and may facilitate the safe use of doxorubicin for cancer treatment.

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Sustained IRE1 and ATF6 signaling is important for survival of melanoma cells undergoing ER stress

Cited by 80 publications

References 38 publications

RIPK1 regulates survival of human melanoma cells upon endoplasmic reticulum stress through autophagy

RIPK1 regulates survival of human melanoma cells upon endoplasmic reticulum stress through autophagy

NELL2 Function in the Protection of Cells against Endoplasmic Reticulum Stress

Chemical Endoplasmic Reticulum Chaperone Alleviates Doxorubicin-Induced Cardiac Dysfunction

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