GRP78 and Raf‐1 cooperatively confer resistance to endoplasmic reticulum stress‐induced apoptosis

Shu, Chih‐Wen; Sun, Fei; Cho, Jun-Hung; Lin, Chih-Chien; Liu, Pei‐Feng; Chen, Ping-Yen; Chang, Margaret Dah‐Tsyr; Fu, Hua-Wen; Lai, Yiu‐Kay

doi:10.1002/jcp.21340

Cited by 69 publications

(57 citation statements)

References 47 publications

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“…Our findings are consistent with this report and add GRP78 to the list of molecular chaperones that are acetylated following inhibition of HDAC6, i.e., HDAC6 "acetylome", which includes a growing list of proteins (36). In transformed cells, activation of the RAS-RAF-MEK-ERK pathway and a basal state of proteotoxic stress induces GRP78 and HDAC6 levels (33,(37)(38)(39). Increased levels of GRP78 also result from an adaptive response to proteotoxic stress and UPR and confer resistance to apoptosis (2,(4)(5)(6)(7)20).…”

Section: Discussionsupporting

confidence: 91%

Treatment with Panobinostat Induces Glucose-Regulated Protein 78 Acetylation and Endoplasmic Reticulum Stress in Breast Cancer Cells

Rao

Nalluri

Kolhe

et al. 2010

Molecular Cancer Therapeutics

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Increased levels of misfolded polypeptides in the endoplasmic reticulum (ER) triggers the dissociation of glucose-regulated protein 78 (GRP78) from the three transmembrane ER-stress mediators, i.e., protein kinase RNA-like ER kinase (PERK), activating transcription factor-6 (ATF6), and inositol-requiring enzyme 1α, which results in the adaptive unfolded protein response (UPR). In the present studies, we determined that histone deacetylase-6 (HDAC6) binds and deacetylates GRP78. Following treatment with the pan-histone deacetylase inhibitor panobinostat (Novartis Pharmaceuticals), or knockdown of HDAC6 by short hairpin RNA, GRP78 is acetylated in 11 lysine residues, which dissociates GRP78 from PERK. This is associated with the activation of a lethal UPR in human breast cancer cells. Coimmunoprecipitation studies showed that binding of HDAC6 to GRP78 requires the second catalytic and COOH-terminal BUZ domains of HDAC6. Treatment with panobinostat increased the levels of phosphorylated-eukaryotic translation initiation factor (p-eIF2α), ATF4, and CAAT/enhancer binding protein homologous protein (CHOP). Panobinostat treatment also increased the proapoptotic BIK, BIM, BAX, and BAK levels, as well as increased the activity of caspase-7. Knockdown of GRP78 sensitized MCF-7 cells to bortezomib and panobinostat-induced UPR and cell death. These findings indicate that enforced acetylation and decreased binding of GRP78 to PERK is mechanistically linked to panobinostat-induced UPR and cell death of breast cancer cells. Mol Cancer Ther; 9(4); 942-52. ©2010 AACR.

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Section: Discussionsupporting

confidence: 91%

Treatment with Panobinostat Induces Glucose-Regulated Protein 78 Acetylation and Endoplasmic Reticulum Stress in Breast Cancer Cells

Rao

Nalluri

Kolhe

et al. 2010

Molecular Cancer Therapeutics

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“…2d). As BIP is a crucial chaperone for cell defence against ER stress [40,41], this finding may explain why blocking NO increased IL-1β + TNF-α + IFN-γ-induced human islet cell death (Fig. 1d).…”

Section: Resultsmentioning

confidence: 95%

“…BIP was the only ER stress marker with significantly decreased expression after inhibition of NO formation. The expression of BIP is crucial for cell defence against ER stress [40,41]. BIP decrease may thus explain the observed increase in IL-1β+ TNF-α+IFN-γ-induced human islet cell death when NO formation is inhibited.…”

Section: Discussionmentioning

confidence: 99%

Cytokines induce endoplasmic reticulum stress in human, rat and mouse beta cells via different mechanisms

et al. 2015

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Aims/hypothesis Proinflammatory cytokines contribute to beta cell damage in type 1 diabetes in part through activation of endoplasmic reticulum (ER) stress. In rat beta cells, cytokineinduced ER stress involves NO production and consequent inhibition of the ER Ca 2+ transporting ATPase sarco/ endoplasmic reticulum Ca 2+ pump 2 (SERCA2B). However, the mechanisms by which cytokines induce ER stress and apoptosis in mouse and human pancreatic beta cells remain unclear. The purpose of this study is to elucidate the role of ER stress on cytokine-induced beta cell apoptosis in these three species and thus solve ongoing controversies in the field. Methods Rat and mouse insulin-producing cells, human pancreatic islets and human EndoC-βH1 cells were exposed to the cytokines IL-1β, TNF-α and IFN-γ, with or without NO inhibition. A global comparison of cytokine-modulated gene expression in human, mouse and rat beta cells was also performed. The chemical chaperone tauroursodeoxycholic acid (TUDCA) and suppression of C/EBP homologous protein (CHOP) were used to assess the role of ER stress in cytokineinduced apoptosis of human beta cells. Results NO plays a key role in cytokine-induced ER stress in rat islets, but not in mouse or human islets. Bioinformatics analysis indicated greater similarity between human and mouse than between human and rat global gene expression after cytokine exposure. The chemical chaperone TUDCA and suppression of CHOP or c-Jun N-terminal kinase (JNK) protected human beta cells against cytokine-induced apoptosis. Conclusions/interpretation These observations clarify previous results that were discrepant owing to the use of islets from different species, and confirm that cytokine-induced ER stress contributes to human beta cell death, at least in part via JNK activation.

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“…59 As local microenvironmental conditions evolve and GRP78 expression increases, melanoma cells gain resistance to intra and extracellular inducers of apoptosis. 60 If increased expression of GRP78 confers resistance to apoptosis, this could help to explain why we observed a decreased overall survival in patients who showed regain of GRP78 at the invasive edge of their melanomas.…”

Section: Discussionmentioning

confidence: 99%

Patterns of GRP78 and MTJ1 expression in primary cutaneous malignant melanoma

et al. 2010

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Cell surface expression of glucose-regulated protein 78 (GRP78) occurs in several types of cancer; however, its role in the behavior of primary cutaneous melanoma is not well studied. The association of cell surface GRP78 with other proteins such as MTJ1 stimulates cell proliferation. In this study, we characterized the pattern of expression of GRP78 and MTJ1 in invasive primary cutaneous melanomas and analyzed the relationships between the pattern of expression and various clinicopathological parameters. We found two patterns of GRP78 expression in invasive primary cutaneous melanoma. One pattern showed a gradual fading of protein expression from superficial to deeper levels within the same tumor. The second pattern of expression showed a similar fading with an abrupt regaining of expression at the deep invasive edge of the melanoma. These two distinct patterns of GRP78 expression correlated with both patient survival and depth of tumor invasion. A moderate MTJ1 expression was found to be associated with decreased patient survival; however, no significant associations were observed between patterns of GRP78 and MTJ1 expression. Our study (1) describes two distinct patterns of GRP78 in invasive primary cutaneous melanoma, (2) inversely correlates regain of GRP78 expression with patient survival, and (3) suggests a modifying effect of MTJ1 on GRP78 in enhancing tumor aggressiveness.

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GRP78 and Raf‐1 cooperatively confer resistance to endoplasmic reticulum stress‐induced apoptosis

Cited by 69 publications

References 47 publications

Treatment with Panobinostat Induces Glucose-Regulated Protein 78 Acetylation and Endoplasmic Reticulum Stress in Breast Cancer Cells

Treatment with Panobinostat Induces Glucose-Regulated Protein 78 Acetylation and Endoplasmic Reticulum Stress in Breast Cancer Cells

Cytokines induce endoplasmic reticulum stress in human, rat and mouse beta cells via different mechanisms

Patterns of GRP78 and MTJ1 expression in primary cutaneous malignant melanoma

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