Endoplasmic Reticulum Stress Signaling as a Therapeutic Target in Malignant Pleural Mesothelioma.

Xu, Duo; Yang, Haitang; Zhang, Yang; Berezowska, Sabina; Gao, Yanyun; Shun-Qing, Liang; Marti, Thomas M.; Hall, Sean R. R.; Dorn, Patrick; Kocher, Gregor J.; Schmid, Ralph A.; Peng, Ren-Wang (2019). Endoplasmic Reticulum Stress Signaling as a Therapeutic Target in Malignant Pleural Mesothelioma. Cancers, 11(10) MDPI AG 10.3390/cancers11101502

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Malignant pleural mesothelioma (MPM) is a lethal cancer with limited treatment options. No targeted therapy has emerged yet. Here, we performed an integrated molecular characterization of patient tumors in the TCGA dataset, and discovered that endoplasmic reticulum (ER) stress and the adaptive unfolded protein response (UPR) signaling are characteristically deregulated in MPM. Consequently, pharmacological perturbation of ER stress/UPR axis by HA15, an agent that induces persistent proteotoxic stress in the ER, selectively suppresses the viability of MPM cells including those refractory to standard chemotherapy. Mechanically, HA15 augments the already high basal level of ER stress in MPM cells, embarks pro-apoptotic malfunctional UPR and autophagy, which eventually induces cell death in MPM. Importantly, HA15 exerts anti-MPM effectiveness in a mouse model of patient-derived xenografts (PDX) without eliciting overt toxicity when compared to chemotherapy. Our results revealed that programs orchestrating ER stress/UPR signaling represent therapeutic vulnerabilities in MPM and validate HA15 as a promising agent to treat patients with MPM, naïve or resistant to chemotherapy.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DCR Services > Central Animal Facility
04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Thoracic Surgery
04 Faculty of Medicine > Service Sector > Institute of Pathology > Molecular Pathology
04 Faculty of Medicine > Service Sector > Institute of Pathology > Clinical Pathology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Forschungsbereich Mu50 > Forschungsgruppe Thoraxchirurgie
04 Faculty of Medicine > Service Sector > Institute of Pathology
04 Faculty of Medicine > Service Sector > Institute of Pathology > Immunohistochemistry
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DCR Services > Core Facility Zytometrie-Labor/FACSlab
04 Faculty of Medicine > Service Sector > Institute of Pathology > Tumour Pathology
04 Faculty of Medicine > Service Sector > Institute of Pathology > Translational Research Unit

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Xu, Duo; Yang, Haitang; Zhang, Yang; Berezowska, Sabina Anna; Gao, Yanyun; Shun-Qing, Liang; Marti, Thomas; Hall, Sean; Dorn, Patrick; Kocher, Gregor; Schmid, Ralph and Peng, Ren-Wang

Subjects:

600 Technology > 610 Medicine & health
500 Science > 570 Life sciences; biology

ISSN:

2072-6694

Publisher:

MDPI AG

Language:

English

Submitter:

Thomas Michael Marti

Date Deposited:

12 Nov 2019 09:32

Last Modified:

12 Nov 2019 09:32

Publisher DOI:

10.3390/cancers11101502

PubMed ID:

31597321

Uncontrolled Keywords:

HA15 autophagy endoplasmic reticulum (ER) stress malignant pleural mesothelioma (MPM) unfolded protein response (UPR)

BORIS DOI:

10.7892/boris.134636

URI:

https://boris.unibe.ch/id/eprint/134636

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