Proteomics

Dataset Information

0

Cooperative treatment effectiveness of VE821 and AUY922 in Ewing’s sarcoma cells


ABSTRACT: Ewing's sarcoma (ES) is the second most frequent bone cancer during childhood and adolescence originating from a translocation between the EWSR1 and the FLI1 gene, which inactivates BRCA-mediated DNA damage response. Both ATR and HSP90 inhibitors are promising new candidates in the field of ES treatment. We show that the HSP90 inhibitor AUY922 alone induced DNA damages, apoptosis and ER stress, while reducing the abundance of DNA repair proteins. The combinations of the ATR inhibitor VE821 and AUY922 (AUY-VE) led to strong apoptosis induction in ES cell lines, originating from a common set of molecular targets and independent of their p53 status, yet based on different molecular mechanisms. P53 wild-type ES cells activated pro-apoptotic gene transcription and underwent mitochondria-mediated apoptosis. P53 null ES cells, however, accumulated higher level of DNA damage, ER stress and autophagy, finally leading to apoptosis. Moreover, AUY-VE treatment compromised ES cell vitality due to impaired PI3K/AKT/mTOR signaling. Unexpectedly, the combinations of AUY922 with the ATM inhibitor, KU55933 failed to kill ES cells and showed protective effects compared to AUY-VE. In summary, we provide mechanistic insights into the effective ES cell killing by ATR and HSP90 inhibitor combinations, which also offers a targetable approach for BRCA-deficient tumors, irrespective of their p53 status and may give rise to new therapeutic strategies.

INSTRUMENT(S): Q Exactive HF-X

ORGANISM(S): Homo Sapiens (human)

DISEASE(S): Peripheral Primitive Neuroectodermal Tumor

SUBMITTER: Joanna Kirkpatrick  

LAB HEAD: Zhao-Qi Wang

PROVIDER: PXD021562 | Pride | 2021-09-09

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
190802_EKS_CM_DDA_AUY922VE821_15.raw Raw
190802_EKS_CM_DDA_AUY922_5.raw Raw
190802_EKS_CM_DDA_VE821_11.raw Raw
190802_EKS_CM_DDA_ctrl_1.raw Raw
190802_EKS_CM_DIA_AUY922VE821_13.raw Raw
Items per page:
1 - 5 of 22
altmetric image

Publications


<h4>Introduction</h4>Ewing's sarcoma is an aggressive childhood malignancy whose outcome has not substantially improved over the last two decades. In this study, combination treatments of the HSP90 inhibitor AUY922 with either the ATR inhibitor VE821 or the ATM inhibitor KU55933 were investigated for their effectiveness in Ewing's sarcoma cells.<h4>Methods</h4>Effects were determined in p53 wild-type and p53 null Ewing's sarcoma cell lines by flow cytometric analyses of cell death, mitochondrial  ...[more]

Similar Datasets

2016-09-01 | GSE85393 | GEO
2016-09-01 | GSE83720 | GEO
2021-10-04 | E-MTAB-8624 | biostudies-arrayexpress
2018-07-16 | PXD008925 | Pride
2015-12-18 | GSE74873 | GEO
2015-12-18 | E-GEOD-74873 | biostudies-arrayexpress
2018-07-17 | PXD010223 | Pride
2022-02-15 | PXD019999 | Pride
2015-05-12 | E-GEOD-55399 | biostudies-arrayexpress
2020-04-14 | PXD017898 | Pride