Implication of Oxygen-Regulated Protein 150 (ORP150) in Apoptosis Induced by Proteasome Inhibitors in Human Thyroid Cancer Cells

Gao, Yanyan; Liu, Bao-Qin; Du, Zhenhong; Zhang, Haiyan; Niu, Xiao-Fang; Wang, Hua‐Qin

doi:10.1210/jc.2010-1043

Cited by 19 publications

(17 citation statements)

References 38 publications

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“…In the SkBr3 breast cancer cell line that abundantly expressed cell surface HER2 (also known as ERBB2), pharmacological inactivation of GRP94 destabilized HER2 and inhibited RAF1-MAPK survival signaling at the cell membrane 72 . In cancer cells, GRP170 is upregulated by hypoxia and by drugs such as celecoxib and proteasome inhibitors, and knockdown of GRP170 activated the expression of the UPR pro-apoptotic factor CHOP and stimulated apoptosis 73,74 . GRP170 may also protect cancer cells against cell death through blocking ER Ca 2+ release or delaying the onset of UPR by binding to the ER stress sensors 75,76 .…”

Section: Biological Functions Of the Grps In Cancermentioning

confidence: 99%

Glucose-regulated proteins in cancer: molecular mechanisms and therapeutic potential

2014

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Preface The glucose regulated proteins (GRPs) are stress inducible chaperones majorly residing in the endoplasmic reticulum (ER) and the mitochondria. Recent advances reveal that the GRPs serve distinct functions from the related heat shock proteins (HSPs), and they can be actively translocated to other cellular locations and assume novel functions controlling signaling, proliferation, invasion, apoptosis, inflammation and immunity. Mouse models further identified their specific roles in development, tumorigenesis, metastasis and angiogenesis. This Review describes their discovery, regulation and their biological functions in cancer. Promising agents using or targeting the GRPs are being developed, and their efficacy as anti-cancer therapeutics is also discussed.

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Section: Biological Functions Of the Grps In Cancermentioning

confidence: 99%

Glucose-regulated proteins in cancer: molecular mechanisms and therapeutic potential

2014

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“…Real-time PCR analysis was performed on the ABI PRISM 7500HT Sequence Detection System using the SYBR Green PCR master mix (ABI). The primer sequences are as follows: for GRP170 the forward primer was 5′-gtgctgcagctcatcaatgac-3′ and reverse was 5′-atctgcagctgtggctgcatc-3′, for BiP the forward primer was 5′- gttcttgccgttcaaggtgg-3′ and reverse was 5′-tggtacagtaacaactgcatg-3′, for β-Actin the forward primer was 5′-gagaccttcaacaccccagcc-3′ and the reverse was 5′-ggatcttcatgaggtagtcag-3′, and for XBP1 (total) the forward primer was 5′-ccaaggggaatgaagtgagg-3′reverse was 5′-aagttgtccagaatgcccaacag-3′ [86].…”

Section: Methodsmentioning

confidence: 99%

UPR-Induced Resistance to Etoposide Is Downstream of PERK and Independent of Changes in Topoisomerase IIα Levels

et al. 2012

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BackgroundThe unfolded protein response (UPR) is regulated by three ER-localized, transmembrane signal transducers that control distinct aspects of the UPR. We previously reported that both increased resistance to etoposide and a reduction in Topoisomerase IIα protein levels were a direct response of UPR activation, and the latter occurred independent of changes in Topo IIα mRNA levels. We have now examined the contribution of each of the three up-stream transducers of the UPR, as well as some of their downstream targets in affecting decreased expression of Topo IIα protein and increased drug resistance.Principal FindingsOur data revealed that while Ire1 activation led to Topo IIα loss at the protein level it did not contribute to changes in sensitivity to etoposide. The decreased expression of Topo IIα protein was not downstream of XBP-1, in keeping with the fact that Topo IIα transcription was not affected by ER stress. Conversely, PERK activation did not contribute to changes in Topo IIα protein levels, but it did play a significant role in the UPR-induced decreased sensitivity to etoposide. Several cellular responses downstream of PERK were examined for their potential to contribute to resistance. The ATF6 arm of the UPR did not significantly contribute to etoposide resistance within the time frame of our experiments.Conclusions and Significance In toto, our data demonstrate that UPR-induced changes in Topo IIα protein levels are not responsible for resistance to etoposide as has been previously hypothesized, and instead demonstrate that the PERK branch plays a Topo IIα-independent role in altered sensitivity to this drug.

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“…GRP170 executes this protective activity by maintaining calcium homeostasis and blocking calcium signaling through IP3 channels ( 67 ). Cytoprotection conferred by induction of GRP170 has also been shown in cellular responses to other ER stressors, e.g., proteasome inhibitors that cause excessive protein accumulation ( 30 , 68 ), hypoxia, ischemia-reperfusion ( 69 – 72 ), and glutamate-induced cytotoxicity ( 73 ). However, the conventional UPR signaling is not the only molecular mechanism involved in the induction of GRP170.…”

Section: Er Stress and Grp170-conferred Cytoprotectionmentioning

confidence: 98%

“…GRP170 consists of 999 amino acids, encoded by hypoxia up-regulated 1 gene ( Hyou1 ) that is located on the q arm of chromosome 11. Beside glucose starvation as a classical inducer of GRPs, including GRP170, other stressors, such as hypoxia, ischemia, perturbation of calcium homeostasis, proteasome inhibitors, and non-steroidal anti-inflammatory drugs (e.g., celecoxib) are also known to upregulate GRP170 expression ( 13 , 30 – 36 ).…”

Section: Grp170 and Its Chaperoning Propertymentioning

confidence: 99%

“…Activated PERK phosphorylates eukaryotic initiation factor 2α (eIF2α), resulting in translation of the ATF4, which also binds to the ERSE sequence to increase the expression GRPs ( 58 ). Both ATF6 and ATF4 have been reported to mediate the UPR-dependent induction of GRP170 due to the existence of ERSE in its gene ( 30 , 31 , 62 , 63 ). The IRE1α induces the unconventional splicing of XBP-1 mRNA and production of the longer isoform of spliced XBP-1 (XBP-1s), which stimulates the transcription of ER chaperone genes, including GRP170 ( 58 , 64 , 65 ).…”

Section: Er Stress and Grp170-conferred Cytoprotectionmentioning

confidence: 99%

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The Endoplasmic Reticulum Chaperone GRP170: From Immunobiology to Cancer Therapeutics

Wang

Pezeshki

et al. 2015

Front. Oncol.

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Glucose-regulated protein 170 (GRP170) is the largest member of glucose-regulated protein family that resides in the endoplasmic reticulum (ER). As a component of the ER chaperone network, GRP170 assists in protein folding, assembly, and transportation of secretory or transmembrane proteins. The well documented cytoprotective activity of intracellular GRP170 due to its intrinsic chaperoning property has been shown to provide a survival benefit in cancer cells during tumor progression or metastasis. Accumulating evidence shows that extracellular GRP170 displays a superior capacity in delivering tumor antigens to specialized antigen-presenting cells for cross-presentation, resulting in generation of an anti-tumor immune response dependent on cytotoxic CD8+ T cells. This unique feature of GRP170 provides a molecular basis for using GRP170 as an immunostimulatory adjuvant to develop a recombinant vaccine for therapeutic immunization against cancers. This review summarizes the latest findings in understanding the biological effects of GRP170 on cell functions and tumor progression. The immunomodulating activities of GRP170 during interactions with the innate and adaptive arms of the immune system as well as its therapeutic applications in cancer immunotherapy will be discussed.

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Implication of Oxygen-Regulated Protein 150 (ORP150) in Apoptosis Induced by Proteasome Inhibitors in Human Thyroid Cancer Cells

Abstract: These results suggest that up-regulation of ORP150 in thyroid cancer cells inhibits MG132-induced apoptosis via suppression of CHOP induction, thereby decreasing the potential antitumor activity of MG132.

Cited by 19 publications

References 38 publications

Glucose-regulated proteins in cancer: molecular mechanisms and therapeutic potential

Glucose-regulated proteins in cancer: molecular mechanisms and therapeutic potential

UPR-Induced Resistance to Etoposide Is Downstream of PERK and Independent of Changes in Topoisomerase IIα Levels

The Endoplasmic Reticulum Chaperone GRP170: From Immunobiology to Cancer Therapeutics

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