The molecular network of the proteasome machinery inhibition response is orchestrated by HSP70, revealing vulnerabilities in cancer cells

Oroń, Magdalena; Grochowski, Marcin; Jaiswar, Akanksha; Legierska, Justyna; Jastrzębski, Kamil; Nowak-Niezgoda, Magdalena; Kołos, Małgorzata; Kaźmierczak, Wojciech; Olesiński, Tomasz; Lenarcik, Małgorzata; Cybulska, Magdalena; Mikula, Michał; Żylicz, Alicja; Miączyńska, Marta; Zettl, K; Wiśniewski, Jacek R.; Walerych, Dawid

doi:10.1016/j.celrep.2022.111428

Cited by 11 publications

(4 citation statements)

References 68 publications

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“…ARF6 may reduce the drug-resistance effects of gemcitabine in PC by increasing the sensitivity of PC cells to iron death [22] . NRF2 inhibitors in combination with siderozotic inducers increase the mortality of gemcitabine-resistant cells [23] . HSPA5 inhibitors promote the degradation of GPX4, thereby enhancing lipid peroxidation during ferroptosis and improving the resistance of PC cells to gemcitabine [24] .…”

Section: Discussionmentioning

confidence: 99%

Identification of the Genetic Association Between Ferroptosis and immune in Pancreatic Cancer

Zhang,

Liu,

et al. 2024

Preprint

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The morbidity and mortality rates of pancreatic cancer are increasing annually. Immunotherapy for pancreatic cancer has not yielded good results, and immunosuppression is now thought to be the key factor. Ferroptosis plays an important role in pancreatic cancer. However, the mechanism of ferroptosis in pancreatic cancer immunosuppression remains unclear. To investigate the relationship between Ferroptosis and immunosuppression in pancreatic cancer.We analyzed differentially expressed genes in the center of pancreatic cancer and pancreatic ductal adenocarcinoma (PDAC) tissues using bioinformatics techniques in the Gene Expression Omnibus and found genes associated with Ferroptosis in the FerrDb database. We then performed enrichment and protein–protein interaction (PPI) network analyses to explore DEG-enriched functions and pathways. Additionally, hub gene expression was explored using the STRING database. The TISIDB database was used to analyze correlations among key genes and immune characteristics. Finally, the expression of the key genes was confirmed in vitro. DEGs were first screened from the gene expression profiles of the GSE16515 and TCGA datasets. Simultaneously, the genes associated with ferroptosis intersected. Then, 39 common genes were identified in the three datasets. Functional analysis revealed that common DEGs were mostly related to lipid metabolism and ROS signaling pathways. Among the top 20 hub genes, CA9 was the most significant potential biomarker of PC. CA9 expression strongly correlates with chemokines, chemokine receptors, and immunomodulators. Finally, RT-qPCR was conducted to demonstrate CA9 expression in PC cell lines. Knockdown of CA9 can significantly reduce chemokines expression. We identified 20 hub genes that significantly affects the association between ferroptosis and PC. CA9 maybe a key player in pancreatic cancer immunosuppression and has potential treatment value for PC.

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Section: Discussionmentioning

confidence: 99%

Identification of the Genetic Association Between Ferroptosis and immune in Pancreatic Cancer

Zhang,

Liu,

et al. 2024

Preprint

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“…A very recent work identifies HSP70 family members as the “managers” of the molecular network of the proteasome machinery, except for controlling Nrf1/2. These results indicate the combination of HSP70 and Nrf1/2 inhibitors as promising therapeutic targets in MM [ 126 ].…”

Section: Hsp70 and Its Targeting In Onco-hematological Diseasesmentioning

confidence: 99%

Is It Still Possible to Think about HSP70 as a Therapeutic Target in Onco-Hematological Diseases?

et al. 2023

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The search for molecules to be targeted that are involved in apoptosis resistance/increased survival and pathogenesis of onco-hematological malignancies is ongoing since these diseases are still not completely understood. Over the years, a good candidate has been identified in the Heat Shock Protein of 70kDa (HSP70), a molecule defined as “the most cytoprotective protein ever been described”. HSP70 is induced in response to a wide variety of physiological and environmental insults, allowing cells to survive lethal conditions. This molecular chaperone has been detected and studied in almost all the onco-hematological diseases and is also correlated to poor prognosis and resistance to therapy. In this review, we give an overview of the discoveries that have led us to consider HSP70 as a therapeutic target for mono- or combination-therapies in acute and chronic leukemias, multiple myeloma and different types of lymphomas. In this excursus, we will also consider HSP70 partners, such as its transcription factor HSF1 or its co-chaperones whose druggability could indirectly affect HSP70. Finally, we will try to answer the question asked in the title of this review considering that, despite the effort made by research in this field, HSP70 inhibitors never reached the clinic.

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“…Once in the nucleus, trimeric HSF1 activates target genes encoding molecular chaperones. A significant interplay between proteasome impairment, oxidative stress, and induction of the heat shock response has been reported [ 168 , 169 ]. In one study, it was discovered that the HSF1 gene could be transcriptionally upregulated by Nrf2 under conditions of oxidative stress in a human fibrosarcoma cell line [ 170 ].…”

Section: Nfe2l1- and Nrf2-dependent Regulation Of Other Proteostasis ...mentioning

confidence: 99%

Role of NFE2L1 in the Regulation of Proteostasis: Implications for Aging and Neurodegenerative Diseases

Chandran,

Oliver,

Rochet

2023

Biology

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A hallmark of aging and neurodegenerative diseases is a disruption of proteome homeostasis (“proteostasis”) that is caused to a considerable extent by a decrease in the efficiency of protein degradation systems. The ubiquitin proteasome system (UPS) is the major cellular pathway involved in the clearance of small, short-lived proteins, including amyloidogenic proteins that form aggregates in neurodegenerative diseases. Age-dependent decreases in proteasome subunit expression coupled with the inhibition of proteasome function by aggregated UPS substrates result in a feedforward loop that accelerates disease progression. Nuclear factor erythroid 2- like 1 (NFE2L1) is a transcription factor primarily responsible for the proteasome inhibitor-induced “bounce-back effect” regulating the expression of proteasome subunits. NFE2L1 is localized to the endoplasmic reticulum (ER), where it is rapidly degraded under basal conditions by the ER-associated degradation (ERAD) pathway. Under conditions leading to proteasome impairment, NFE2L1 is cleaved and transported to the nucleus, where it binds to antioxidant response elements (AREs) in the promoter region of proteasome subunit genes, thereby stimulating their transcription. In this review, we summarize the role of UPS impairment in aging and neurodegenerative disease etiology and consider the potential benefit of enhancing NFE2L1 function as a strategy to upregulate proteasome function and alleviate pathology in neurodegenerative diseases.

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The molecular network of the proteasome machinery inhibition response is orchestrated by HSP70, revealing vulnerabilities in cancer cells

Cited by 11 publications

References 68 publications

Identification of the Genetic Association Between Ferroptosis and immune in Pancreatic Cancer

Identification of the Genetic Association Between Ferroptosis and immune in Pancreatic Cancer

Is It Still Possible to Think about HSP70 as a Therapeutic Target in Onco-Hematological Diseases?

Role of NFE2L1 in the Regulation of Proteostasis: Implications for Aging and Neurodegenerative Diseases

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