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

Martin, Shaun; Lamb, Heather K.; Brady, Conor; Lefkove, Benjamin; Bonner, Michael Y.; Thompson, Paul R.; Lovat, Penny E.; Arbiser, Jack L.; Hawkins, Alastair R.; Redfern, Christopher P.F.

doi:10.1038/bjc.2013.325

Cited by 82 publications

(67 citation statements)

References 36 publications

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“…Recent studies have concluded that EGCG has binding affinity to the nucleotide binding (ATPase) domain of GRP78 and once bound, EGCG inhibits GRP78 association with ATP by competitive inhibition [15,16]. Thus, it inhibits the ATPase activity of GRP78.…”

Section: Inhibitors Against Grp78mentioning

confidence: 99%

“…EGCG and OSU-03012 binding to GRP78: some mechanistic insights Differential scanning calorimetry experiments indicate that EGCG binds to unfolded form of GRP78 NBD [16]. These authors mention in their paper, BIt is likely that, by analogy with HSP-70 (Liu et al, 2010), an intrinsic mobility of the GRP78 N-terminal domain unfolds it sufficiently to facilitate access of EGCG or HNK under prolonged incubation conditions of a few hours or more^.…”

Section: Molecular Dynamics Simulationsmentioning

confidence: 99%

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Molecular docking and molecular dynamics studies reveal structural basis of inhibition and selectivity of inhibitors EGCG and OSU-03012 toward glucose regulated protein-78 (GRP78) overexpressed in glioblastoma

2015

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Glioblastoma (GBM), a malignant form of brain tumor, has a high mortality rate. GRP78, one of the HSP70 protein family members, is overexpressed in GBM. GRP78 is the key chaperone protein involved in the unfolded protein response. Upregulated GRP78 expression in cancer cells inhibits apoptosis and promotes chemoresistance. GRP78 has an ATPase domain, a substrate-binding domain, and a linker region. ATP-competitive inhibitors such as EGCG and OSU-03012 inhibit GRP78 activity and reduce its expression in GBM. However, there is a lack of structural data on the binding modes of these inhibitors to GRP78 ATPase domain. Further, the mode of selectivity of these inhibitors toward GRP78 also is unknown. Toward this end, molecular docking was performed with AutoDock Vina and confirmation obtained by docking using ROSIE. The stability and MM-PBSA binding energy of GRP78-inhibitor complexes as well as energetic contribution of individual residues was analyzed by 50 ns molecular dynamics run with GROMACS. MSA by ClustalW2 identified unique amino acid residues in the ATPase domain of GRP78 which were different from the residues present in other HSP70 proteins. Important and unique amino acid residues of GRP78 such as Ile61, Glu293, Arg297, and Arg367 played a major role in the intermolecular interactions with these inhibitors. The interactions with unique residues of GRP78 as compared with those of HSP70-1A provided the basis for selectivity. It was found that the binding affinity and specificity/selectivity of EGCG toward GRP78 was higher than that toward HSP70-1A, and selectivity was even better than OSU-03012. OSU-03012 was predicted to bind to GRP78. Analyses from MD runs showed tight binding and stability of complexes, and the highest number of hydrogen bonds during the trajectory runs were comparable to those found in the docking studies. Energetic contribution of individual inhibitor-interacting residues showed that energy values of Ile61 and Glu293 were among the most negative. These studies are, to the best of our knowledge, the first studies characterizing EGCG and OSU-03012 interactions with GRP78 on a structural basis and provide a significant insight into their binding modes, selectivity, and structural stability.

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Section: Inhibitors Against Grp78mentioning

confidence: 99%

Section: Molecular Dynamics Simulationsmentioning

confidence: 99%

Molecular docking and molecular dynamics studies reveal structural basis of inhibition and selectivity of inhibitors EGCG and OSU-03012 toward glucose regulated protein-78 (GRP78) overexpressed in glioblastoma

2015

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“…4,5 Surprisingly, p53 mutations are very rare in melanoma, but activity is, however, impaired through direct or indirect inactivation of key elements of this pathway, including through the suppression of APAF-1 expression, 6 loss of PTEN function, 7 dysregulation of Bcl-2 expression, 8 upregulation of the anti-apoptotic protein Mcl-1 together with its altered slice variant expression 9,10 and the ER chaperone GRP78. [11][12][13] Oncogenic mutations, however, in the Ras/Raf pathway are the most well-described genetic mutations associated with melanoma development and progression. 14 Indeed, up to 90% of all melanomas harbour activating NRAS or BRAF mutations, with BRAF V600E representing more than 90% of BRAF mutations, 15,16 the consequence of which is the constitutive activation of RAF-extracellular signal-regulated kinase/ERK signalling promoting melanoma proliferation and resistance to apoptosis.…”

mentioning

confidence: 99%

Oncogenic BRAF induces chronic ER stress condition resulting in increased basal autophagy and apoptotic resistance of cutaneous melanoma

et al. 2014

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The notorious unresponsiveness of metastatic cutaneous melanoma to current treatment strategies coupled with its increasing incidence constitutes a serious worldwide clinical problem. Moreover, despite recent advances in targeted therapies for patients with BRAF V600E mutant melanomas, acquired resistance remains a limiting factor and hence emphasises the acute need for comprehensive pre-clinical studies to increase the biological understanding of such tumours in order to develop novel effective and longlasting therapeutic strategies. Autophagy and ER stress both have a role in melanoma development/progression and chemoresistance although their real impact is still unclear. Here, we show that BRAF V600E induces a chronic ER stress status directly increasing basal cell autophagy. BRAF V600E -mediated p38 activation stimulates both the IRE1/ASK1/JNK and TRB3 pathways. Bcl-XL/Bcl-2 phosphorylation by active JNK releases Beclin1 whereas TRB3 inhibits the Akt/mTor axes, together resulting in an increase in basal autophagy. Furthermore, we demonstrate chemical chaperones relieve the BRAF V600E -mediated chronic ER stress status, consequently reducing basal autophagic activity and increasing the sensitivity of melanoma cells to apoptosis. Taken together, these results suggest enhanced basal autophagy, typically observed in BRAF V600E melanomas, is a consequence of a chronic ER stress status, which ultimately results in the chemoresistance of such tumours. Targeted therapies that attenuate ER stress may therefore represent a novel and more effective therapeutic strategy for BRAF mutant melanoma.

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“…However, the present study did not review the experimental literature concerning patients with osteosarcoma. In addition, numerous studies have demonstrated that GRP78 represents a concordant mechanism of drug resistance in malignant tumors, and could therefore be applied as a predictor for guiding the treatment for patients (11,(20)(21)(22)(23). The present study aimed to investigate the expression of GRP78 in patients with osteosarcoma, and to analyze the expressional differences in tumor tissue and normal tissue, chemotherapy-and non-chemotherapy-treated patients, and metastatic and non-metastatic tumors.…”

Section: Introductionmentioning

confidence: 99%

“…In view of its importance for the survival of cancer cells, GRP78 could be used as an anticancer drug target. Certain anticancer compounds, such as plant-derived genistein, (-)-Epigallocatechin gallate, honokiol and salicylic acid could be used to inhibit the expression or activity of GRP78 (21)(22)(23).…”

Section: Introductionmentioning

confidence: 99%

Expression and significance of glucose-regulated protein 78 in human osteosarcoma

Zhang

Wang

et al. 2015

Oncology Letters

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Abstract. The present study aimed to investigate the expression of glucose-regulated protein 78 (GRP78) in osteosarcoma cells, and analyze the differences in expression between tumor and normal tissues, pre-and post-chemotherapy patients and metastatic and non-metastatic tumors. According to these results, the associations between the expression of GRP78 and tumor growth, metastasis and chemotherapeutics could be determined. Between 2007 and 2012, 60 patients who had been diagnosed with osteosarcoma were selected for the present study. Of these patients, 20 presented with non-metastatic tumors and 40 with metastatic tumors, and 20 had been treated without chemotherapy and 40 with chemotherapy. In addition, 60 specimens obtained from adjacent normal tissues were collected for the control groups. Immunofluorescence staining was used to examine the expression of GRP78 in the different tissues. The total RNA and protein were extracted from crushed tissues and used in the reverse transcription polymerase chain reaction and western blot analysis. GRP78 was primarily located in the intracavity of the endoplasmic reticulum. The expression level of GRP78 in the tumor tissue was higher than that in the normal tissue surrounding the tumor (P<0.01). In addition, the level was higher in the metastatic tumors compared with the non-metastatic tumors (P<0.05), and in the non-chemotherapy-treated patients compared with the chemotherapy-treated patients (P<0.01). The expression level of GRP78 mRNA in the tumor tissue was higher than that in the normal tissue (P<0.01). Furthermore, the level was higher in the metastasis group than in the non-metastasis group (P<0.05), and in the non-chemotherapy group than in the chemotherapy group (P<0.01). The expression level of GRP78 protein was higher in the tumor tissue compared with the normal tissue (P<0.01), in the metastasis group compared with the non-metastasis group (P<0.05), and in the non-chemotherapy group compared with the chemotherapy group (P<0.01). In conclusion, the present study detected the expression of GRP78 in patients with osteosarcoma and revealed a higher expression level in the tumor tissues compared with the normal tissues around the tumor, in the metastasis group compared with the non-metastasis group and in the non-chemotherapy-treated group compared with the chemotherapy-treated group.

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

Cited by 82 publications

References 36 publications

Molecular docking and molecular dynamics studies reveal structural basis of inhibition and selectivity of inhibitors EGCG and OSU-03012 toward glucose regulated protein-78 (GRP78) overexpressed in glioblastoma

Molecular docking and molecular dynamics studies reveal structural basis of inhibition and selectivity of inhibitors EGCG and OSU-03012 toward glucose regulated protein-78 (GRP78) overexpressed in glioblastoma

Oncogenic BRAF induces chronic ER stress condition resulting in increased basal autophagy and apoptotic resistance of cutaneous melanoma

Expression and significance of glucose-regulated protein 78 in human osteosarcoma

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