Dataset Information

Inducing apoptosis of cancer cells using small-molecule plant compounds that bind to GRP78.

ABSTRACT:

Background

Glucose regulated protein 78 (GRP78) functions as a sensor of endoplasmic reticulum (ER) stress. The aim of this study was to test the hypothesis that molecules that bind to GRP78 induce the unfolded protein response (UPR) and enhance cell death in combination with ER stress inducers.

Methods

Differential scanning calorimetry (DSC), measurement of cell death by flow cytometry and the induction of ER stress markers using western blotting.

Results

Epigallocatechin gallate (EGCG), a flavonoid component of Green Tea Camellia sinensis, and honokiol (HNK), a Magnolia grandiflora derivative, bind to unfolded conformations of the GRP78 ATPase domain. Epigallocatechin gallate and HNK induced death in six neuroectodermal tumour cell lines tested. Levels of death to HNK were twice that for EGCG; half-maximal effective doses were similar but EGCG sensitivity varied more widely between cell types. Honokiol induced ER stress and UPR as predicted from its ability to interact with GRP78, but EGCG was less effective. With respect to cell death, HNK had synergistic effects on melanoma and glioblastoma cells with the ER stress inducers fenretinide or bortezomib, but only additive (fenretinide) or inhibitory (bortezomib) effects on neuroblastoma cells.

Conclusion

Honokiol induces apoptosis due to ER stress from an interaction with GRP78. The data are consistent with DSC results that suggest that HNK binds to GRP78 more effectively than EGCG. Therefore, HNK may warrant development as an antitumour drug.

SUBMITTER: Martin S

PROVIDER: S-EPMC3721410 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Publications

Inducing apoptosis of cancer cells using small-molecule plant compounds that bind to GRP78.

Martin S S Lamb H K HK Brady C C Lefkove B B Bonner M Y MY Thompson P P Lovat P E PE Arbiser J L JL Hawkins A R AR Redfern C P F CP

British journal of cancer 20130627 2

<h4>Background</h4>Glucose regulated protein 78 (GRP78) functions as a sensor of endoplasmic reticulum (ER) stress. The aim of this study was to test the hypothesis that molecules that bind to GRP78 induce the unfolded protein response (UPR) and enhance cell death in combination with ER stress inducers.<h4>Methods</h4>Differential scanning calorimetry (DSC), measurement of cell death by flow cytometry and the induction of ER stress markers using western blotting.<h4>Results</h4>Epigallocatechin ...[more]

PMID: 23807168

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Project description:Pluripotent stem cells can be induced from somatic cells, providing an unlimited cell resource for regenerative medicine. However, genetic manipulation and difficult-to-manufacture strategies used in reprogramming limit their clinical applications. Here, we show pluripotency can be induced from mouse somatic cells by specific small-molecule compounds. The completely chemically-induced pluripotent stem cells (CiPSCs) can be stably maintained in embryonic stem cell (ESC) culture medium and resemble ESCs in terms of their gene expression profiles, epigenetic status, and potential for differentiation and germline transmission. These findings suggest that exogenous master genes are dispensable for cell fate reprogramming and pave the way for the clinical application of somatic reprogramming techniques. Pluripotent stem cells can be induced from somatic cells, providing an unlimited cell resource for regenerative medicine. However, genetic manipulation and difficult-to-manufacture strategies used in reprogramming limit their clinical applications. Here, we show pluripotency can be induced from mouse somatic cells by specific small-molecule compounds. The completely chemically-induced pluripotent stem cells (CiPSCs) can be stably maintained in embryonic stem cell (ESC) culture medium and resemble ESCs in terms of their gene expression profiles, epigenetic status, and potential for differentiation and germline transmission. These findings suggest that exogenous master genes are dispensable for cell fate reprogramming and pave the way for the clinical application of somatic reprogramming techniques. Chemicals' acronyms: V, VPA; C, CHIR; 6, 616452; T, tranylcypromine; F, FSK; Z, DZNep; P, PGE2; R, RG108; S, SRT1720; M, 2-Me-5HT; D, D4476; B, Sodium butyrate. To compare the global gene expression pofile of mouse embryonic fibroblasts (MEFs), mouse adult lung fibroblasts (MAFs), mouse neonatal fibroblasts (MNFs), adipose-derived stem cells (ADSCs), chemical induced pluripotent stem cells (CiPS), embryonic stem cells (ESCs) and OSKM-iPSCs. We profiled the mRNA expression of each sample by microarray (Mouse OneArray® v2, Phalanx). Different sample set was normalized for different purpose. Set1: MEFs1, CiPS34, MNF CIPS7, CiPS50 CiPS21, OSKM-iPS1 and ESCs1 were analyzed, each sample have three replicates; Set2: MNFs, MAFs, ADSCs, MNF CiPS1, MAF CiPS3, CiPS45, ADSC CiPS2, OSKM iPS2 and ESCs2 were analyzed, each sample have three replicates; Set3: WT MEFs, ESCs3, CiPS WT1 and CiPS WT2 were analyzed, each sample have two replicates; Set4: MEFs2, SKM-FSK1, SKM-FSK2 and ESCs4 were analyzed, each sample have three replicates; Set5: MEFs3, ESCs5, CiPSCs, D12, D20 and D32 were analyzed, each sample have two replicates.

Dataset Information

Inducing apoptosis of cancer cells using small-molecule plant compounds that bind to GRP78.

Background

Methods

Results

Conclusion

Publications

Inducing apoptosis of cancer cells using small-molecule plant compounds that bind to GRP78.

Similar Datasets

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