ER stress sensor, glucose regulatory protein 78 (GRP78) regulates redox status in pancreatic cancer thereby maintaining “stemness”

Dauer, Patricia; Sharma, Nikita; Gupta, Vineet; Durden, Brittany; Hadad, Roey; Banerjee, Santanu; Dudeja, Vikas; Saluja, Ashok K.; Banerjee, Sulagna

doi:10.1038/s41419-019-1408-5

Cited by 80 publications

(70 citation statements)

References 56 publications

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“…Additionally, in head and neck squamous cell carcinoma, the GRP78/p-PEK/NRF2 signaling pathway was found to promote the Warburg effect (domination of glycolysis over oxidative phosphorylation), being critical for the maintenance of both low ROS levels and the CSC-like phenotype in tumor-initiating cells [235]. Studies of the effects of shRNA/GRP78 on pancreatic cancer cells have revealed that GRP78, as the ER stress sensor and redox regulator, promotes self-renewal and tumorigenicity while preventing oxidative stress and thus maintaining cancer stemness [236].…”

Section: Intracellular Grp78mentioning

confidence: 99%

Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

Kabakov

Yakimova

Matchuk

2020

Cells

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Cancer stem cells (CSCs) are a great challenge in the fight against cancer because these self-renewing tumorigenic cell fractions are thought to be responsible for metastasis dissemination and cases of tumor recurrence. In comparison with non-stem cancer cells, CSCs are known to be more resistant to chemotherapy, radiotherapy, and immunotherapy. Elucidation of mechanisms and factors that promote the emergence and existence of CSCs and their high resistance to cytotoxic treatments would help to develop effective CSC-targeting therapeutics. The present review is dedicated to the implication of molecular chaperones (protein regulators of polypeptide chain folding) in both the formation/maintenance of the CSC phenotype and cytoprotective machinery allowing CSCs to survive after drug or radiation exposure and evade immune attack. The major cellular chaperones, namely heat shock proteins (HSP90, HSP70, HSP40, HSP27), glucose-regulated proteins (GRP94, GRP78, GRP75), tumor necrosis factor receptor-associated protein 1 (TRAP1), peptidyl-prolyl isomerases, protein disulfide isomerases, calreticulin, and also a transcription heat shock factor 1 (HSF1) initiating HSP gene expression are here considered as determinants of the cancer cell stemness and potential targets for a therapeutic attack on CSCs. Various approaches and agents are discussed that may be used for inhibiting the chaperone-dependent development/manifestations of cancer cell stemness.

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Section: Intracellular Grp78mentioning

confidence: 99%

Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

Kabakov

Yakimova

Matchuk

2020

Cells

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“…Given the roles of GRP78 in regulating PI3K−Akt activity and endoplasmic reticulum (ER) oxidative stress [13,21], we next examined whether induced targeting of PTEN with p85α in the lipid raft membranes by TSWU-BR4 was associated with delocalization of GRP78 from the membrane to the cytosol. Flow cytometric analysis showed that the cell surface localization of GRP78 was suppressed, which was associated with an increased level of cytosolic GRP78 by TSWU-BR4 ( Figure 4A and Supplementary Figure S1).…”

Section: Tswu-br4-induced Dissociation Of Grp78 and P85α Leads To Thementioning

confidence: 99%

“…ER is also recognized as a major site of the biosynthesis of cholesterol and lipids [17], as evidenced by involvement of GRP78 in regulating lipid metabolism of cancer cells and its localization in ER [18]. Additionally, GRP78 modulates antioxidant activities of glutathione and NAD(P)H:quinone oxidoreductase by inducing activation of protein kinase RNA-like endoplasmic reticulum kinase and nuclear factor erythroid 2 p45-related factor 2 [19], contributing the protection of cancer cells from oxidative stress-induced damage [20,21]. Increased formation of cell surface GRP78−PI3K complexes in cancer cells confers a beneficial effects on cell survival and resistance to reactive oxygen species (ROS)-induced lipotoxicity [13,22].…”

Section: Introductionmentioning

confidence: 99%

Impairment of Membrane Lipid Homeostasis by Bichalcone Analog TSWU-BR4 Attenuates Function of GRP78 in Regulation of the Oxidative Balance and Invasion of Cancer Cells

Lee

Wang

Chan

et al. 2020

Cells

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The specialized cholesterol/sphingolipid-rich membrane domains termed lipid rafts are highly dynamic in the cancer cells, which rapidly assemble effector molecules to form a sorting platform essential for oncogenic signaling transduction in response to extra- or intracellular stimuli. Density-based membrane flotation, subcellular fractionation, cell surface biotinylation, and co-immunoprecipitation analyses of bichalcone analog ((E)-1-(4-Hydroxy-3-((4-(4-((E)-3-(pyridin-3-yl)acryloyl)phenyl)piperazin-1-yl)methyl)phenyl)-3-(pyridin-3-yl)prop-2-en-1-one (TSWU-BR4)-treated cancer cells showed dissociation between GRP78 and p85α conferring the recruitment of PTEN to lipid raft membranes associated with p85α. Ectopic expression of GRP78 could overcome induction of lipid raft membrane-associated p85α–unphosphorylated PTEN complex formation and suppression of GRP78−PI3K−Akt−GTP-Rac1-mediated and GRP78-regulated PERK−Nrf2 antioxidant pathway and cancer cell invasion by TSWU-BR4. Using specific inducer, inhibitor, or short hairpin RNA for ASM demonstrated that induction of the lipid raft membrane localization and activation of ASM by TSWU-BR4 is responsible for perturbing homeostasis of cholesterol and ceramide levels in the lipid raft and ER membranes, leading to alteration of GRP78 membrane trafficking and subsequently inducing p85α–unphosphorylated PTEN complex formation, causing disruption of GRP78−PI3K−Akt−GTP-Rac1-mediated signal and ER membrane-associated GRP78-regulated oxidative stress balance, thus inhibiting cancer cell invasion. The involvement of the enrichment of ceramide to lipid raft membranes in inhibition of NF-κB-mediated MMP-2 expression was confirmed through attenuation of NF-κB activation using C2-ceramide, NF-κB specific inhibitors, ectopic expression of NF-κB p65, MMP-2 promoter-driven luciferase, and NF-κB-dependent reporter genes. In conclusion, localization of ASM in the lipid raft membranes by TSWU-BR4 is a key event for initiating formation of ceramide-enriched lipid raft membrane platforms, which causes delocalization of GRP78 from the lipid raft and ER membranes to the cytosol and formation of p85α–unphosphorylated PTEN complexes to attenuate the GRP78-regulated oxidative stress balance and GRP78−p85α−Akt−GTP-Rac1−NF-κB−MMP-2-mediated cancer cell invasion.

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“…As a broad specificity molecular chaperone within ER, binding immunoglobulin protein (Bip), also known as 78-kDa glucose regulated protein (GRP78), correctly folds nascent polypeptides and regulates the unfolded protein response (UPR) ensuring protection of the cell from denatured protein and reinforcing its anti-apoptotic role, when the cell is under stress 11 . In addition, Bip is responsible for maintaining "stemness" in cancer cells 12,13 . To demonstrate the mechanism of GSCs resistance to IR-induced ICD, the role of Bip was evaluated in ER stress-activated ICD.…”

Section: Introductionmentioning

confidence: 99%

Bip inhibition in glioma stem cells promotes radiation-induced immunogenic cell death

Yang

Xiu

et al. 2020

Cell Death Dis

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Tumor regression in sites distant to the irradiated field are thought to be associated with emission of damage-associated molecular patterns (DAMPs) molecules and generation of immunogenic cell death (ICD). Glioma stem cells (GSCs) are resistant to high doses of radiation, and ultimately select the outgrowth of a more aggressive tumor. This study showed high-dose IR triggered fewer DAMPs molecules exposure and release in GSCs comparing to matched non-GSCs. Downregulation of binding immunoglobulin protein (Bip) promoted IR-mediated endoplasmic reticulum stress to generate DAMPs molecules by PERK and IRE1-α phosphorylation, and increased dendritic cells mature and effector T lymphocytes activation. GSCs treated with Bip knockdown and IR efficiently prevented tumor generation, and reduced post-radiotherapy tumor recurrence. These data suggest that Bip plays a critical role in inhibition of IR-induced ICD in GSCs, and Bip inhibition may be a promising strategy on adjuvant therapy by ameliorating tumor immune microenvironment.

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ER stress sensor, glucose regulatory protein 78 (GRP78) regulates redox status in pancreatic cancer thereby maintaining “stemness”

Cited by 80 publications

References 56 publications

Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

Impairment of Membrane Lipid Homeostasis by Bichalcone Analog TSWU-BR4 Attenuates Function of GRP78 in Regulation of the Oxidative Balance and Invasion of Cancer Cells

Bip inhibition in glioma stem cells promotes radiation-induced immunogenic cell death

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