Effect of Beclin-1 gene silencing on autophagy and apoptosis of the prostatic hyperplasia epithelial cells

Liu, Rongfu; Zhang, Song; Wu, Rui; Deng, Jing; Fang, Wei

doi:10.1016/j.clinsp.2022.100076

Cited by 3 publications

(2 citation statements)

References 33 publications

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“…A protein of high significance in the study of autophagy is Beclin-1/Atg6, which regulates the autophagy-apoptosis axis through interaction with the Bcl-2 antiapoptotic protein family (66,67). Beclin-1 accumulation was observed to drop after treatment with a low dose of Bortezomib (20 nM; however, at the high, toxic dose of 40 nM, its accumulation increased, indicating the induction of autophagy due to severe UPS impairment.…”

Section: Resultsmentioning

confidence: 99%

“…An important role in this process was attributed to Beclin-1, which was also overexpressed in resistant cells. Aside from the regulation of autophagy, it has been found to directly interact with the Bcl-2 anti-apoptotic protein family, thus acting cytoprotectively (35,66,67). The modulation of signaling molecules with known cytoprotective roles was evident in the resistant clone, mainly focusing on Hsp70 and the stress-related kinases p38 and JNK1 (70,71,94,102).…”

Section: Discussionmentioning

confidence: 99%

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The ERK1/2-Elk1, JNK-cJun, and JAK-STAT Transcriptional Axes as Potential Bortezomib Resistance Mediators in Prostate Cancer

Kalampounias,

Zafeiropoulou,

Androutsopoulou

et al. 2024

Preprint

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The effectiveness of proteasome inhibitors against solid tumors is limited as the emergence of resistance is rapid. Although many mechanisms have been proposed and verified, no definite answer has been given, highlighting the complexity of the resistant phenotype. In this study, a Bortezomib-resistant prostate cancer cell line is created, and a broad-spectrum signaling pathway analysis is performed to identify differences and adaptations the resistant cells exhibit. Our findings highlight the upregulation and activation of Nf-κB, STAT3, cJun, and Elk1 transcription factors in the resistant cells and the subsequent evasion of apoptosis and induction of autophagy, which is constantly activated and substitutes the role of the ubiquitin-proteasome system (UPS). Additionally, assessment of the intracellular reactive oxygen species in resistant cells confirms their downregulation, which is theorized to be a consequence of metabolic changes, increased autophagic flux, and antioxidative enzyme action. The results of this study highlight the potential therapeutic targeting of key kinases and transcription factors, participating in the main signaling pathways and gene regulation of Bortezomib-resistant cells, that could re-sensitize the cells to proteasome inhibitors, thus surpassing the current limitations.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The ERK1/2-Elk1, JNK-cJun, and JAK-STAT Transcriptional Axes as Potential Bortezomib Resistance Mediators in Prostate Cancer

Kalampounias,

Zafeiropoulou,

Androutsopoulou

et al. 2024

Preprint

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Autophagy and oxidative stress modulation mediate Bortezomib resistance in prostate cancer

Zafeiropoulou,

Kalampounias,

Alexis

et al. 2024

PLoS ONE

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Proteasome inhibitors such as Bortezomib represent an established type of targeted treatment for several types of hematological malignancies, including multiple myeloma, Waldenstrom’s macroglobulinemia, and mantle cell lymphoma, based on the cancer cell’s susceptibility to impairment of the proteasome-ubiquitin system. However, a major problem limiting their efficacy is the emergence of resistance. Their application to solid tumors is currently being studied, while simultaneously, a wide spectrum of hematological cancers, such as Myelodysplastic Syndromes show minimal or no response to Bortezomib treatment. In this study, we utilize the prostate cancer cell line DU-145 to establish a model of Bortezomib resistance, studying the underlying mechanisms. Evaluating the resulting resistant cell line, we observed restoration of proteasome chymotrypsin-like activity, regardless of drug presence, an induction of pro-survival pathways, and the substitution of the Ubiquitin-Proteasome System role in proteostasis by induction of autophagy. Finally, an estimation of the oxidative condition of the cells indicated that the resistant clones reduce the generation of reactive oxygen species induced by Bortezomib to levels even lower than those induced in non-resistant cells. Our findings highlight the role of autophagy and oxidative stress regulation in Bortezomib resistance and elucidate key proteins of signaling pathways as potential pharmaceutical targets, which could increase the efficiency of proteasome-targeting therapies, thus expanding the group of molecular targets for neoplastic disorders.

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Identification of biomarkers related to prostatic hyperplasia based on bioinformatics and machine learning

Ying¹,

Zhao²,

2023

MBE

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<abstract> <p>In older adults, benign prostatic hyperplasia (BPH) is the most common cause of lower urinary tract symptoms (LUTS). This study aimed to explore the genes with diagnostic value in patients with BPH, reveal the relationship between the expression of diagnosis-related genes and the immune microenvironment, and provide a reference for molecular diagnosis and immunotherapy of BPH. The combined gene expression data of GSE6099, GSE7307 and GSE119195 in the GEO database were used. The differential expression of autophagy-related genes between BPH patients and healthy controls was obtained by differential analysis. Then the genes related to BPH diagnosis were screened by a machine learning algorithm and verified. Finally, five important genes (IGF1, PSIP1, SLC1A3, SLC2A1 and T1A1) were obtained by random forest (RF) algorithm, and their relationships with the immune microenvironment were discussed. Five genes play an essential role in the occurrence and development of BPH and may become new diagnostic markers of BPH. Among them, immune cells have significant correlation with some genes. The signal transduction of IL-4 mediated by M2 macrophages is closely related to the progress of BPH. There are abundant active mast cells in BPH. The adoption and metastasis of regulatory T cells may be an important method to treat BPH.</p> </abstract>

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Effect of Beclin-1 gene silencing on autophagy and apoptosis of the prostatic hyperplasia epithelial cells

Cited by 3 publications

References 33 publications

The ERK1/2-Elk1, JNK-cJun, and JAK-STAT Transcriptional Axes as Potential Bortezomib Resistance Mediators in Prostate Cancer

The ERK1/2-Elk1, JNK-cJun, and JAK-STAT Transcriptional Axes as Potential Bortezomib Resistance Mediators in Prostate Cancer

Autophagy and oxidative stress modulation mediate Bortezomib resistance in prostate cancer

Identification of biomarkers related to prostatic hyperplasia based on bioinformatics and machine learning

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