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The ambiguous role of obesity in oncology by promoting cancer but boosting antitumor immunotherapy.

Obesity is nowadays considered a pandemic which prevalence's has been steadily increasingly in western countries. It is a dynamic, complex, and multifactorial disease which propitiates the development of several metabolic and cardiovascular diseases, as well as cancer. Excessive adipose tissue has been causally related to cancer progression and is a preventable risk factor for overall and cancer-specific survival, associated with poor prognosis in cancer patients. The onset of obesity features a state of chronic low-grade inflammation and secretion of a diversity of adipocyte-derived molecules

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… When proteins accumulate in ER lumen, the homeostatic mechanism unfolded protein response (UPR) is initiated [ 59 ], leading to ROS formation and ER stress [ 60 ]. … Adams CJ Kopp MC Larburu N Nowak PR Ali MMU Structure and molecular mechanism of ER stress signaling by the unfolded protein response signal activator IRE1 Front Mol Biosci 2019 6 1 12 30931312 10.3389/fmolb.2019.00011 PMC6423427 61. …

Role of mitochondria in physiological activities, diseases, and therapy.

Mitochondria are generally considered essential for life in eukaryotic organisms because they produce most of the energy or adenosine triphosphate (ATP) needed by the cell. Beyond energy production, it is now widely accepted that mitochondria also play a pivotal role in maintaining cellular homeostasis and signaling. The two core processes of mitochondrial dynamics, fission and fusion, serve as crucial foundations for maintaining mitochondrial morphology, distribution, and quantity, thereby ensuring cellular homeostasis. Mitochondrial autophagy (mitophagy) ensures the selective degradation of

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… MQC mechanisms include mitochondrial proteases, the mitochondrial unfolded protein response (UPR), mitochondria-derived vesicles (MDVs), and mitophagy [ 254 , 255 ]. …

Epigenetic mechanisms in cardiovascular complications of diabetes: towards future therapies.

The pathophysiological mechanisms of cardiovascular disease and microvascular complications in diabetes have been extensively studied, but effective methods of prevention and treatment are still lacking. In recent years, DNA methylation, histone modifications, and non-coding RNAs have arisen as possible mechanisms involved in the development, maintenance, and progression of micro- and macro-vascular complications of diabetes. Epigenetic changes have the characteristic of being heritable or deletable. For this reason, they are now being studied as a therapeutic target for the treatment of diabe

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… Nat Struct Mol Biol. 2012;19(12):1218–27. 23211769 10.1038/nsmb.2436 PMC3645987 Nakajima S Kitamura M Bidirectional regulation of NF-kappaB by reactive oxygen species: a role of unfolded protein response Free Radic Biol Med 2013 65 162 74 10.1016/j.freeradbiomed.2013.06.020 23792277 Nakajima S, Kitamura … Bidirectional regulation of NF-kappaB by reactive oxygen species: a role of unfolded protein response. Free Radic Biol Med. 2013;65:162–74. 23792277 10.1016/j.freeradbiomed.2013.06.020 Nathan DM, Cleary PA, Backlund JY, Genuth SM, Lachin JM, Orchard TJ, Raskin P, Zinman B, Diabetes C et al. …

Proteasomal adaptations to FDA-approved proteasome inhibitors: a potential mechanism for drug resistance?

With proteasome inhibitors (PIs) becoming clinically available since 2003, outcomes for patients with multiple myeloma (MM) have dramatically changed, improving quality of life and survival. Despite the impressive treatment success, however, almost all MM patients who initially respond to these PIs eventually develop resistance. Furthermore, a portion of MM patients is inherently unresponsive to the PIs. Extensive mechanistic investigations identified several non-proteasomal signaling pathways suspected to be linked to the PI resistance, for which several excellent reviews are currently availa

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… Extensive mechanistic investigations identified several non-proteasomal PI resistance mechanisms, such as those involving dysregulations of unfolded protein response, autophagy, aggresomes, MARCKS proteins, or efflux transporters [ 16 - 23 ] . …

Специфические сети miRNA-mRNA в серой и белой материи из прогрессивных множественных склерозов.

ЦЕЛЬ: Множественный склероз (MS) — нейродегенеративное демиелинирующее заболевание центральной нервной системы. Цель этого исследования заключалась в выявлении сетей регулирования микро-РНК (миРНК)-мРНК, лежащих в основе региональных молекулярных механизмов в белой материи и повреждения серы в прогрессивных MS. МЕТОДЫ: Глобальное miRNA и mRNA профилирование выражений ранее проводилось на белых и серых тканях, поврежденных после смерти прогрессивных умов MS. Эти наборы данных были интегрированы с помощью анализа Ингенитетных путей (ИПА) для выявления обогащенных канонических путей на основе экс

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… Saxena , “ ER Stress and the Unfolded Protein Response in Neurodegeneration ,” Nature Reviews. Neurology 13 , no. 8 ( 2017 ): 477 – 491 . 28731040 10.1038/nrneurol.2017.99 41 Y. Chen , R. B. Kunjamma , K. …

Repurposing of nervous system drugs for cancer treatment: recent advances, challenges, and future perspectives.

The nervous system plays a critical role in developmental biology and oncology, influencing processes from ontogeny to the complex dynamics of cancer progression. Interactions between the nervous system and cancer significantly affect oncogenesis, tumor growth, invasion, metastasis, treatment resistance, inflammation that promotes tumors, and the immune response. A comprehensive understanding of the signal transduction pathways involved in cancer biology is essential for devising effective anti-cancer strategies and overcoming resistance to existing therapies. Recent advances in cancer neurosc

Bone sialoprotein: a multifunctional regulator of bone remodelling and tumour progression.

Bone sialoprotein (BSP) is a major non-collagenous protein of the bone extracellular matrix and an important regulator of bone formation and resorption. BSP is produced by bone cells and chondrocytes and present in the bone matrix, cells, dentin and cartilage. However, its aberrant expression in primary tumour tissues and the sera of cancer patients with metastases implicates BSP in tumour biology and progression. The Arg-Gly-Asp (RGD) motif of BSP may be crucial not only for the attachment of metastasising cells to the bone surface but also for tumour growth, survival and activity. This revie

Dietary factors and their influence on immunotherapy strategies in oncology: a comprehensive review.

Immunotherapy is emerging as a promising avenue in oncology, gaining increasing importance and offering substantial advantages when compared to chemotherapy or radiotherapy. However, in the context of immunotherapy, there is the potential for the immune system to either support or hinder the administered treatment. This review encompasses recent and pivotal studies that assess the influence of dietary elements, including vitamins, fatty acids, nutrients, small dietary molecules, dietary patterns, and caloric restriction, on the ability to modulate immune responses. Furthermore, the article und

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… LPD reportedly triggers the unfolded protein response in cancer cells, leading to the activation of the IRE1α and RIG1 signaling pathways [ 68 ]. This induces the production of cytokines, stimulating an efficient anticancer immune response. …

Human-Induced Pluripotent Stem Cell Models for Amyloid Cardiomyopathy: From Mechanistic Insights to Therapeutic Discovery.

Amyloid cardiomyopathy (ACM), driven by transthyretin (TTR) and immunoglobulin light chain (LC) amyloid fibrils, remains a major clinical challenge due to limited mechanistic understanding and insufficient preclinical models. Human-induced pluripotent stem cells (iPSCs) have emerged as a transformative platform to model ACM, offering patient-specific and genetically controlled systems. In this review, we summarize recent advances in the use of iPSC-derived cardiomyocytes (iPSC-CMs) in both two-dimensional (2D) monolayer cultures and three-dimensional (3D) constructs-including spheroids, organo

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… The study also demonstrated that activation of the activating transcription factor 6 (ATF6) branch of the unfolded protein response could preferentially suppress the secretion of amyloidogenic TTR without affecting the secretion of wild-type TTR [ 77 ]. … Overexpression often required crossing onto mouse TTR-knockout backgrounds or deletion of stress-response regulators (e.g., HSF1) to achieve fibrillogenesis, revealing how hepatic unfolded protein response (UPR) and chaperone dynamics modulate deposition [ 120 , 121 ]. …

Cyanobacterial Peptides in Anticancer Therapy: A Comprehensive Review of Mechanisms, Clinical Advances, and Biotechnological Innovation.

Cyanobacteria-derived peptides represent a promising class of anticancer agents due to their structural diversity and potent bioactivity. They exert cytotoxic effects through mechanisms including microtubule disruption, histone deacetylase inhibition, and apoptosis induction. Several peptides-most notably the dolastatin-derived auristatins-have achieved clinical success as cytotoxic payloads in antibody-drug conjugates (ADCs). However, challenges such as limited tumor selectivity, systemic toxicity, and production scalability remain barriers to broader application. Recent advances in targeted

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… The resulting protein overload triggers the unfolded protein response and other stress pathways; if the damage becomes overwhelming, the cell undergoes apoptosis due to proteotoxic stress and cell-cycle arrest. … Additionally, the mislocalization of normally secreted proteins triggers ER stress and an unfolded protein response, which can culminate in apoptosis [ 31 ]. Another cyanobacterial compound, coibamide A, also targets the Sec61 translocon [ 52 ]. …

H727 cells are inherently resistant to the proteasome inhibitor carfilzomib, yet require proteasome activity for cell survival and growth.

The second-in-class proteasome inhibitor (PI) carfilzomib (Kyprolis, Cfz) has contributed to a substantial advancement in multiple myeloma treatment by improving patient survival and quality of life. A considerable portion of patients however display intrinsic resistance to Cfz. Our mechanistic understanding of intrinsic Cfz resistance is limited due to a lack of suitable cell-based models. We report that H727 human bronchial carcinoid cells are inherently resistant to Cfz, yet susceptible to other PIs and inhibitors targeting upstream components of the ubiquitin-proteasome system (UPS). These

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… Dahlqvist J, Torma H, Badhai J, Dahl N. siRNA silencing of proteasome maturation protein (POMP) activates the unfolded protein response and constitutes a model for KLICK genodermatosis. PLoS One. 2012;7:e29471. doi: 10.1371/journal.pone.0029471. 31. Murata S, Yashiroda H, Tanaka K. …

Nifuroxazide induces the apoptosis of human non‑small cell lung cancer cells through the endoplasmic reticulum stress PERK signaling pathway.

The aim of the present study was to investigate the molecular mechanism of nifuroxazide (NFZ) in the induction of apoptosis of NCI-H1299 human non-small cell lung cancer (NSCLC) cells through the reactive oxygen species (ROS)/Ca2+/protein kinase R-like ER kinase (PERK)-activating transcription factor 4 (ATF4)-DNA damage inducible transcript 3 (CHOP) signaling pathway. Morphological changes of cells were observed by microscopy, and the apoptosis and intracellular ROS levels of cells were observed by inverted fluorescence microscopy. Cell viability after the addition of the PERK inhibitor, GSK26

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… Emerging roles of the endoplasmic reticulum associated unfolded protein response in cancer cell migration and invasion. Cancers (Basel) 2019;11:631. doi: 10.3390/cancers11050631. 31. Oakes SA. Endoplasmic reticulum stress signaling in cancer cells. …

Disease Milestones through Bibliometric Analysis of the Top 100 Cited Articles in Multiple Myeloma.

Multiple myeloma (MM) accounts for 1.6% of all cancers and 5%-10% of all hematologic malignancies in the United States (US). Despite marked progress in disease management, it remains incurable with high rates of relapse. We conducted a bibliographic analysis on the Web of Science (WOS) from July 25, 2017 and July 29, 2017. Among the top 100 most-cited articles (1901-2012), the most cited article received 2404 citations and least cited article received 336 citations. Forty-four of 100 articles were published in journals with impact factors greater than 20. We observed that over the years, the f

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… . | Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells | Blood 2006;107(4907);16507771 | 483 47 | Matsui, W et al. | Characterization of clonogenic multiple myeloma cells | Blood 2004;103(2332);14630803 | 477 48 | Rajkumar, SV et al. | Lenalidomide plus high-dose …

Chronic Psychological Stress in Oncogenesis: Multisystem Crosstalk and Multimodal Interventions.

Malignant tumors constitute a major global public health burden. Chronic psychological stress (CPS) manifests as sustained dysregulation arising from prolonged adaptive responses to chronic endogenous and exogenous stimuli. Clinical evidence indicates that CPS markedly influences cancer progression, with most oncology patients developing detectable stress-related psychological disorders during disease management. This review synthesizes recent advances in understanding CPS-mediated oncogenic mechanisms and evaluates current intervention approaches. Mechanistically, CPS compromises immune surve

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… The subsequent activation of the unfolded protein response, an originally protective cellular mechanism, is exploited by cancer cells to enhance their survival, dissemination, and resistance to therapy [ 87 ]. …

Influence of Hypoxia on Tumor Heterogeneity, DNA Repair, and Cancer Therapy: From Molecular Insights to Therapeutic Strategies.

Hypoxia, characterized by a reduction in tissue oxygen levels, is a hallmark of many solid tumors and affects a range of cellular processes, including DNA repair. In low-oxygen conditions, cancer cells often suppress key DNA repair pathways such as homologous recombination (HR), leading to the accumulation of DNA damage and increased genomic instability. These changes not only drive tumor progression but also contribute to resistance against conventional therapies. Hypoxia significantly reduces the effectiveness of oxygen-dependent treatments, including radiotherapy and many chemotherapeutic a

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… As a significant cellular stressor, severe hypoxia triggers the unfolded protein response (UPR) and inhibits global mRNA translation, reducing cellular activity and making cells less susceptible to damage from radiation [ 140 ]. 4.2. … What is also worth mentioning in the context of chemoresistance development is that in hypoxic conditions, chronic endoplasmic reticulum (ER) stress leads to activation of the unfolded protein response (UPR) in tumor cells—a mechanism protecting cells from protein homeostasis disruption. …

Hepatotoxicity Profile of Bortezomib-Containing Regimens for First-Line Multiple Myeloma Treatment.

Background/Objectives: Bortezomib, a proteasome inhibitor, is one of the key agents in the first-line treatment of multiple myeloma (MM). Although its hepatotoxic potential has been described in case reports and registration trials, systematic real-life studies quantifying the incidence, dynamics and prognostic significance of liver injury during bortezomib-based therapy are lacking. We aimed to characterize the hepatotoxicity profile of first-line bortezomib-based regimens. Methods: We retrospectively analyzed 115 consecutively treated MM patients at University Hospital Dubrava (2016-2023) wh

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… Beyond disrupted NF-κB signaling, additional mechanisms proposed to contribute to proteasome inhibitor-associated hepatic injury include accumulation of misfolded proteins with endoplasmic reticulum stress and activation of the unfolded protein response, mitochondrial dysfunction, generation of reactive …

A malignant symbiosis: The neuro-metabolic symphony rewires the tumor microenvironment.

Emerging evidence in cancer neuroscience has established a reciprocal bidirectional loop between neural signaling and tumor metabolism as a central driver of malignant progression. This review critically evaluates bidirectional neuro-metabolic symbiosis and its profound implications for overcoming treatment refractoriness. We first analyzed the anterograde mechanism, in which peripheral nerve terminals and systemic endocrine factors impose distinct metabolic dependencies on malignant and stromal cell populations. By forcing alterations in nutrient utilization pathways, these neural cues create

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… Melatonin activates the unfolded protein response via the PERK-ATF4 pathway, initiating apoptosis and suppressing choriocarcinoma development [ 113 ]. …

High-dose intravenous vitamin C, a promising multi-targeting agent in the treatment of cancer.

Mounting evidence indicates that vitamin C has the potential to be a potent anti-cancer agent when administered intravenously and in high doses (high-dose IVC). Early phase clinical trials have confirmed safety and indicated efficacy of IVC in eradicating tumour cells of various cancer types. In recent years, the multi-targeting effects of vitamin C were unravelled, demonstrating a role as cancer-specific, pro-oxidative cytotoxic agent, anti-cancer epigenetic regulator and immune modulator, reversing epithelial-to-mesenchymal transition, inhibiting hypoxia and oncogenic kinase signalling and b

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… protein response and inhibition of the cell translation (eIF2α, PKR/PKR pThr-446) - apoptotic process | [ 161 ] Neuroblastoma | SH-SY5Y cell line | SUMO-1 IP followed by ESI-FT ICR MS | 30 min treatment with 100 μM ascorbate (or 100 μM hydrogen peroxide) | – | low | Identify redox sensitive proteins … Specifically, eIF2α and PKR/PKR pThr-446 were suggested to be responsible for the unfolded protein response and inhibition of cell translation during endoplasmic reticulum stress, which may be a direct result of increased oxidative stress. …

The Inclusion of Dietary and Medicinal Mushrooms into Translational Oncology: Pros and Cons at the Molecular Level.

Mushrooms are valued for their nutritional qualities and have been used in traditional medicine since the Neolithic era. They exhibit various bioactivities, including antioxidant, hypocholesterolemic, immunomodulatory, and anticancer effects. The anticancer effects arise via direct action on tumor cells and indirect modulation of the immune system; the latter is the predominant mechanism. Numerous studies indicate that various mushroom species are potent immunostimulants because their cell wall polysaccharides and proteoglycans are recognized by intestinal immune cells. This enhances antitumor

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… The most commonly altered pathways include the PI3K/AKT/mTOR and MAPK (RTK/RAS), which promote oncogenic growth and survival; the Wnt/β-catenin, which regulates stemness and proliferation; the p53, which mediates genomic integrity and apoptosis; and the unfolded protein response (UPR), which manages … Additionally, the authors proposed that cordycepin induces unfolded protein response-dependent cell death, though this occurs only at high concentrations [ 279 ]. Several studies have demonstrated that cordycepin, an adenosine analog, is an agonist of adenosine receptors (ADORA). …

Targeting the Ubiquitin-Proteasome System for Cancer Therapeutics by Small-Molecule Inhibitors.

The ubiquitin-proteasome system (UPS) is a critical regulator of cellular protein levels and activity. It is, therefore, not surprising that its dysregulation is implicated in numerous human diseases, including many types of cancer. Moreover, since cancer cells exhibit increased rates of protein turnover, their heightened dependence on the UPS makes it an attractive target for inhibition via targeted therapeutics. Indeed, the clinical application of proteasome inhibitors in treatment of multiple myeloma has been very successful, stimulating the development of small-molecule inhibitors targetin

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… Small-Molecule RA-9 Inhibits Proteasome-Associated DUBs and Ovarian Cancer In Vitro and In Vivo via Exacerbating Unfolded Protein Responses. Clin. Cancer Res. 2014;20:3174–3186. doi: 10.1158/1078-0432.CCR-13-2658. 44. Kapuria V., Peterson L.F., Fang D., Bornmann W.G., Talpaz M., Donato N.J. …