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  • Original Article
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Enhanced selenium effect on growth arrest by BiP/GRP78 knockdown in p53-null human prostate cancer cells

Abstract

Redox modification of thiol/disulfide interchange in proteins by selenium could lead to protein unfolding. When this occurs in the endoplasmic reticulum (ER), a process known as unfolded protein response (UPR) is orchestrated for survival through activation of PERK–eIF2α (PERK: double-stranded RNA-activated protein kinase-like ER kinase; eIF2α: eucaryotic initiation factor 2α), ATFα (ATFα: activating transcription factor 6) and inositol requiring 1 (IRE1)-x-box-binding protein 1 (XBP1) signalings. All three UPR transducer pathways were upregulated very rapidly when PC-3 cells were exposed to selenium. These changes were accompanied by increased expression of UPR target genes, including immunoglobulin heavy chain-binding protein/glucose-regulated protein, 78 kDa and CCAAT/enhancer binding protein-homologous protein/growth arrest- and DNA damage-inducible gene (CHOP/GADD153). Induction of BiP/GRP78, an ER-resident chaperone, is part of the damage control mechanism, while CHOP/GADD153 is a transcription factor associated with growth arrest and apoptosis in the event of prolonged ER stress. Knocking down BiP/GRP78 induction by small interference RNA produced a differential response of the three transducers to selenium, suggesting that the signaling intensity of each transducer could be fine-tuned depending on BiP/GRP78 availability. In the presence of selenium, CHOP/GADD153 expression was raised even higher by BiP/GRP78 knockdown. Under this condition, the selenium effect on wild-type p53-activated fragment p21 (p21WAF), cyclin-dependent kinase (CDK)1 and CDK2 was also magnified in a manner consistent with enhanced cell growth arrest. Additional experiments with CHOP/GADD153 siRNA knockdown strongly suggested that CHOP/GADD153 may play a positive role in upregulating the expression of p21WAF in a p53-independent manner (PC-3 cells are p53 null). Collectively, the above findings support the idea that UPR could be an important mechanism in mediating the anticancer activity of selenium.

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Abbreviations

ATF6:

activating transcription factor 6

BiP/GRP78:

immunoglobulin heavy chain-binding protein/glucose-regulated protein, 78 kDa

BrdU:

5-bromo-2′-deoxyuridine

CDK:

cyclin-dependent kinase

CHOP/GADD153:

CCAAT/enhancer binding protein-homologous protein/growth arrest- and DNA damage-inducible gene

EDEM:

endoplasmic reticulum degradation-enhancing alpha-mannosidase-like protein

eIF2α:

eucaryotic initiation factor 2α

ER:

endoplasmic reticulum

ERSE:

ER stress response element

ESI:

electrospray ionization

GLS:

Golgi localization sequences

IRE1:

inositol requiring 1

MSA:

methylseleninic acid

MALDI-TOF:

matrix-assisted laser desorption ionization-time-of-flight

p21WAF:

wild-type p53-activated fragment p21

p58IPK:

protein kinase inhibitor p58

PERK:

double-stranded RNA-activated protein kinase-like ER kinase

RNase:

ribonuclease

RT–PCR:

reverse transcription–polymerase chain reaction

siRNA:

small interference RNA

UPR:

unfolded protein response

XBP1:

x-box-binding protein 1

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Acknowledgements

This work was supported by Grant CA 09796 from the National Cancer Institute and Grant 62-2198 from the Roswell Park Alliance Foundation, and was partially supported by core resources of the Roswell Park Cancer Institute Cancer Center Support Grant P30 CA 16056 from the National Cancer Institute.

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Zu, K., Bihani, T., Lin, A. et al. Enhanced selenium effect on growth arrest by BiP/GRP78 knockdown in p53-null human prostate cancer cells. Oncogene 25, 546–554 (2006). https://doi.org/10.1038/sj.onc.1209071

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