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

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

doi:10.3390/cancers11101502

Cited by 26 publications

(26 citation statements)

References 43 publications

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“…There is a positive correlation between expression of the ER stress-responsive phosphatase growth arrest and DNA damage 34 (GADD34) and differentiation status of mesothelial cells (83), suggesting that modulating ER stress might be effective for MPM. Consistently, we have recently showed that deregulated ER stress/UPR is a characteristic feature of MPM, and that therapeutic modulation of the signaling impairs the growth of MPM cells and overcomes resistance to standard chemotherapy (84,85).…”

Section: Endoplasmic Reticulum (Er) Stress and Unfolded Protein Resposupporting

confidence: 60%

Therapeutic Landscape of Malignant Pleural Mesothelioma: Collateral Vulnerabilities and Evolutionary Dependencies in the Spotlight

Yang

Schmid

et al. 2020

Front. Oncol.

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Malignant pleural mesothelioma (MPM) is the epitome of a recalcitrant cancer driven by pharmacologically intractable tumor suppressor proteins. A significant but largely unmet challenge in the field is the translation of genetic information on alterations in tumor suppressor genes (TSGs) into effective cancer-specific therapies. The notion that abnormal tumor genome subverts physiological cellular processes, which creates collateral vulnerabilities contextually related to specific genetic alterations, offers a promising strategy to target TSG-driven MPM. Moreover, emerging evidence has increasingly appreciated the therapeutic potential of genetic and pharmacological dependencies acquired en route to cancer development and drug resistance. Here, we review the most recent progress on vulnerabilities co-selected by functional loss of major TSGs and dependencies evolving out of cancer development and resistance to cisplatin based chemotherapy, the only first-line regimen approved by the US Food and Drug Administration (FDA). Finally, we highlight CRISPR-based functional genomics that has emerged as a powerful platform for cancer drug discovery in MPM. The repertoire of MPM-specific "Achilles heel" rises on the horizon, which holds the promise to elucidate therapeutic landscape and may promote precision oncology for MPM.

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Section: Endoplasmic Reticulum (Er) Stress and Unfolded Protein Resposupporting

confidence: 60%

Therapeutic Landscape of Malignant Pleural Mesothelioma: Collateral Vulnerabilities and Evolutionary Dependencies in the Spotlight

Yang

Schmid

et al. 2020

Front. Oncol.

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“…It has been reported that HA15, a novel inhibitor targeting GRP78, could upregulate ER stress levels in malignant pleural mesothelioma cells, induce the pro-apoptotic UPR and autophagy, and induce cell death ( Xu et al, 2019 ). Similarly, lung cancer cell apoptosis induced by HA15 was concomitant with ER stress.…”

Section: Discussionmentioning

confidence: 99%

“…HA15-induced apoptosis is not only related closely to ER stress but also to autophagy ( Cerezo et al, 2016 ; Xu et al, 2019 ). Analogously, we found that HA15 treatment of the lung cancer cell line, A549, activated autophagy and triggered formation of autophagosomes.…”

Section: Discussionmentioning

confidence: 99%

Targeted inhibition of GRP78 by HA15 promotes apoptosis of lung cancer cells accompanied by ER stress and autophagy

Lian

2020

Biology Open

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This study aimed to investigate the pathophysiological role of GRP78 in the survival of lung cancer cells. Lung cancer patient data from public databases were used to analyze the expression of GRP78 and its influence on prognoses. In vivo, GRP78 protein expression was analyzed in an established urethane-induced lung tumor mouse model. In vitro, the effects of targeted inhibition of GRP78 by HA15 in lung cancer cells were assessed, with cell viability analyzed using a CCK-8 assay, cell proliferation using an EdU assay, apoptosis and cell cycle using flow cytometry, subcellular structure using electron microscopy, and relative mRNA and protein expression using RT-PCR, western blotting or immunofluorescence assay. The results showed that GRP78 was highly expressed in the lung tissue of lung cancer mice model or patients, and was associated with a poor prognosis. After inhibition of GRP78 in lung cancer cells by HA15, cell viability was decreased in a dose- and time-dependent manner, proliferation was suppressed and apoptosis promoted. Unfolded protein response signaling pathway proteins were activated, and the autophagy-related proteins and mRNAs were upregulated. Therefore, targeted inhibition of GRP78 by HA15 promotes apoptosis of lung cancer cells accompanied by ER stress and autophagy.

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“…Although earlier studies had suggested the existence of two different anatomical sites for the niche (periosteal and perivascular), preponderant evidence now favors the existence of only the latter [70]. The niche comprises hematopoietic stem cells (HSCs), hematopoietic progenitor cells (HPCs), and a variety of other components [vascular endothelial cells, C-X-C motif chemokine 12 (CXCL12)-abundant reticular cells, mesenchymal stromal cells (MSCs), adipocytes that form the BM microenvironment [38]. BM microenvironment cells nurture HSCs/HPCs via the production of a wide variety of factors (chemokines, cytokines), thereby providing the signals that lead to HSCs/HPCs survival, replication, and differentiation into all the mature blood cells [71].…”

Section: Upr In Hematopoietic and Leukemic Stem Cellsmentioning

confidence: 99%

The Unfolded Protein Response: A Novel Therapeutic Target in Acute Leukemias

Martelli

Paganelli

Chiarini

et al. 2020

Cancers

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The unfolded protein response (UPR) is an evolutionarily conserved adaptive response triggered by the stress of the endoplasmic reticulum (ER) due, among other causes, to altered cell protein homeostasis (proteostasis). UPR is mediated by three main sensors, protein kinase RNA-like endoplasmic reticulum kinase (PERK), activating transcription factor 6α (ATF6α), and inositol-requiring enzyme-1α (IRE1α). Given that proteostasis is frequently disregulated in cancer, UPR is emerging as a critical signaling network in controlling the survival, selection, and adaptation of a variety of neoplasias, including breast cancer, prostate cancer, colorectal cancer, and glioblastoma. Indeed, cancer cells can escape from the apoptotic pathways elicited by ER stress by switching UPR into a prosurvival mechanism instead of cell death. Although most of the studies on UPR focused on solid tumors, this intricate network plays a critical role in hematological malignancies, and especially in multiple myeloma (MM), where treatment with proteasome inhibitors induce the accumulation of unfolded proteins that severely perturb proteostasis, thereby leading to ER stress, and, eventually, to apoptosis. However, UPR is emerging as a key player also in acute leukemias, where recent evidence points to the likelihood that targeting UPR-driven prosurvival pathways could represent a novel therapeutic strategy. In this review, we focus on the oncogene-specific regulation of individual UPR signaling arms, and we provide an updated outline of the genetic, biochemical, and preclinical therapeutic findings that support UPR as a relevant, novel target in acute leukemias.

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

Cited by 26 publications

References 43 publications

Therapeutic Landscape of Malignant Pleural Mesothelioma: Collateral Vulnerabilities and Evolutionary Dependencies in the Spotlight

Therapeutic Landscape of Malignant Pleural Mesothelioma: Collateral Vulnerabilities and Evolutionary Dependencies in the Spotlight

Targeted inhibition of GRP78 by HA15 promotes apoptosis of lung cancer cells accompanied by ER stress and autophagy

The Unfolded Protein Response: A Novel Therapeutic Target in Acute Leukemias

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