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Advanced Science (Weinheim,... Apr 2024Photodynamic therapy (PDT) is a minimally invasive and controllable local cancer treatment for cholangiocarcinoma (CCA). However, the efficacy of PDT is hindered by...
Photodynamic therapy (PDT) is a minimally invasive and controllable local cancer treatment for cholangiocarcinoma (CCA). However, the efficacy of PDT is hindered by intratumoral hypoxia and the presence of an antioxidant microenvironment. To address these limitations, combining PDT with gas therapy may be a promising strategy to enhance tumor oxygenation. Moreover, the augmentation of oxidative damage induced by PDT and gas therapy can be achieved by inhibiting NRF2, a core regulatory molecule involved in the antioxidant response. In this study, an integrated nanotherapeutic platform called CMArg@Lip, incorporating PDT and gas therapies using ROS-responsive liposomes encapsulating the photosensitizer Ce6, the NO gas-generating agent L-arginine, and the NRF2 inhibitor ML385, is successfully developed. The utilization of CMArg@Lip effectively deals with challenges posed by tumor hypoxia and antioxidant microenvironment, resulting in elevated levels of oxidative damage and subsequent induction of ferroptosis in CCA. Additionally, these findings suggest that CMArg@Lip exhibits notable immunomodulatory effects, including the promotion of immunogenic cell death and facilitation of dendritic cell maturation. Furthermore, it contributes to the anti-tumor function of cytotoxic T lymphocytes through the downregulation of PD-L1 expression in tumor cells and the activation of the STING signaling pathway in myeloid-derived suppressor cells, thereby reprogramming the immunosuppressive microenvironment via various mechanisms.
Topics: Humans; Photochemotherapy; NF-E2-Related Factor 2; Antioxidants; Cholangiocarcinoma; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Tumor Microenvironment
PubMed: 38308097
DOI: 10.1002/advs.202307143 -
International Journal of Biological... 2023Colorectal cancer (CRC) driven by deficiency exhibits high risk of metastasis, advancement of tumor stages and chemotherapy resistance, where no effective therapy has...
Colorectal cancer (CRC) driven by deficiency exhibits high risk of metastasis, advancement of tumor stages and chemotherapy resistance, where no effective therapy has been developed. In this study, we performed a synthetic lethal drug screening in CRC and found that PTEN-deficient CRC cells are highly vulnerable to MDM2 inhibition. MDM2 inhibitor treatment or its silencing selectively inhibited the growth of PTEN-deficient CRC in vitro and in mice models. Mechanistically, PTEN loss increased the level of active AKT and subsequently increased MDM2 phosphorylation, thereby limiting the p53 functions in CRC cells. MDM2 inhibition in turn activated p53 in CRC, particularly in CRC cells. The synthetic lethal effect of MDM2 inhibitor was largely dependent on p53, because p53 silenced cells or cells lacking p53 failed to exhibit synthetic lethality in PTEN-deficient cells. We further showed that MDM2 inhibition led to the p53-dependent reversal of Bcl2-Bax ratio, which contributed to mitochondria-mediated apoptotic cell death in PTEN-deficient CRC. This study suggests that pharmacological targeting of MDM2 could be a potential therapeutic strategy for PTEN-deficient CRC.
Topics: Animals; Mice; Antineoplastic Agents; Cell Line, Tumor; Colorectal Neoplasms; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-mdm2; Tumor Suppressor Protein p53
PubMed: 37496993
DOI: 10.7150/ijbs.82566 -
Cell Death & Disease Jan 2024Endoplasmic reticulum (ER) stress induces the unfolded protein response (UPR), and prolonged ER stress leads to cell apoptosis. Despite increasing research in this area,...
Endoplasmic reticulum (ER) stress induces the unfolded protein response (UPR), and prolonged ER stress leads to cell apoptosis. Despite increasing research in this area, the underlying molecular mechanisms remain unclear. Here, we discover that ER stress upregulates the UPR signaling pathway while downregulating E2F target gene expression and inhibiting the G2/M phase transition. Prolonged ER stress decreases the mRNA levels of E2F2, which specifically regulates the expression of F-Box Protein 5(FBXO5), an F-box protein that functions as an inhibitor of the anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase complex. Depletion of FBXO5 results in increased ER stress-induced apoptosis and decreased expression of proteins related to PERK/IRE1α/ATF6 signaling. Overexpression of FBXO5 wild-type (not its ΔF-box mutant) alleviates apoptosis and the expression of the C/EBP Homologous Protein (CHOP)/ATF. Mechanistically, we find that FBXO5 directly binds to and promotes the ubiquitin-dependent degradation of RNF183, which acts as a ubiquitin E3 ligase in regulating ER stress-induced apoptosis. Reversal of the apoptosis defects caused by FBXO5 deficiency in colorectal cancer cells can be achieved by knocking down RNF183 in FBXO5-deficient cells. Functionally, we observed significant upregulation of FBXO5 in colon cancer tissues, and its silencing suppresses tumor occurrence in vivo. Therefore, our study highlights the critical role of the FBXO5/RNF183 axis in ER stress regulation and identifies a potential therapeutic target for colon cancer treatment.
Topics: Humans; Protein Serine-Threonine Kinases; Endoribonucleases; Endoplasmic Reticulum Stress; Unfolded Protein Response; Ubiquitin; F-Box Proteins; Colonic Neoplasms; Apoptosis; Cell Cycle Proteins; Ubiquitin-Protein Ligases
PubMed: 38212299
DOI: 10.1038/s41419-024-06421-2 -
Biomedicine & Pharmacotherapy =... May 2024Emerging research into metabolic dysfunction-associated steatotic liver disease (MASLD) up until January 2024 has highlighted the critical role of cuproptosis, a unique... (Review)
Review
Emerging research into metabolic dysfunction-associated steatotic liver disease (MASLD) up until January 2024 has highlighted the critical role of cuproptosis, a unique cell death mechanism triggered by copper overload, in the disease's development. This connection offers new insights into MASLD's complex pathogenesis, pointing to copper accumulation as a key factor that disrupts lipid metabolism and insulin sensitivity. The identification of cuproptosis as a significant contributor to MASLD underscores the potential for targeting copper-mediated pathways for novel therapeutic approaches. This promising avenue suggests that managing copper levels could mitigate MASLD progression, offering a fresh perspective on treatment strategies. Further investigations into how cuproptosis influences MASLD are essential for unraveling the detailed mechanisms at play and for identifying effective interventions. The focus on copper's role in liver health opens up the possibility of developing targeted therapies that address the underlying causes of MASLD, moving beyond symptomatic treatment to tackle the root of the problem. The exploration of cuproptosis in the context of MASLD exemplifies the importance of understanding metal homeostasis in metabolic diseases and represents a significant step forward in the quest for more effective treatments. This research direction lights path for innovative MASLD management and reversal.
Topics: Animals; Humans; Copper; Fatty Liver; Insulin Resistance; Lipid Metabolism; Liver; Metabolic Diseases; Apoptosis
PubMed: 38615611
DOI: 10.1016/j.biopha.2024.116585 -
Advanced Science (Weinheim,... May 2024A recently emerging cell death pathway, known as copper-induced cell death, has demonstrated significant potential for treating infections. Existing research suggests...
A recently emerging cell death pathway, known as copper-induced cell death, has demonstrated significant potential for treating infections. Existing research suggests that cells utilizing aerobic respiration, as opposed to those reliant on glycolysis, exhibit greater sensitivity to copper-induced death. Herein, a MnO-loaded copper metal-organic frameworks platform is developed denoted as MCM, to enhance bacterial cuproptosis-like death via the remodeling of bacterial respiratory metabolism. The reversal of hypoxic microenvironments induced a cascade of responses, encompassing the reactivation of suppressed immune responses and the promotion of osteogenesis and angiogenesis. Initially, MCM catalyzed O production, alleviating hypoxia within the biofilm and inducing a transition in bacterial respiration mode from glycolysis to aerobic respiration. Subsequently, the sensitized bacteria, characterized by enhanced tricarboxylic acid cycle activity, underwent cuproptosis-like death owing to increased copper concentrations and aggregated intracellular dihydrolipoamide S-acetyltransferase (DLAT). The disruption of hypoxia also stimulated suppressed dendritic cells and macrophages, thereby strengthening their antimicrobial activity through chemotaxis and phagocytosis. Moreover, the nutritional effects of copper elements, coupled with hypoxia alleviation, synergistically facilitated the regeneration of bones and blood vessels. Overall, reshaping the infection microenvironment to enhance cuproptosis-like cell death presents a promising avenue for eradicating biofilms.
Topics: Biofilms; Animals; Copper; Mice; Oxides; Manganese Compounds; Disease Models, Animal; Hypoxia
PubMed: 38477452
DOI: 10.1002/advs.202308850 -
ESC Heart Failure Dec 2023Mechanochemical signalling drives organogenesis and is highly conserved in mammal evolution. Regaining recovery in myocardial jeopardy by inducing principles linking...
AIMS
Mechanochemical signalling drives organogenesis and is highly conserved in mammal evolution. Regaining recovery in myocardial jeopardy by inducing principles linking cardiovascular therapy and clinical outcome has been the dream of scientists for decades. Concepts involving embryonic pathways to regenerate adult failing hearts became popular in the early millennium. Since then, abundant data on stem cell research have been published, never reaching widespread application in heart failure therapy. Another conceptual access, using mechanotransduction in cardiac veins to limit myocardial decay, is pressure-controlled intermittent coronary sinus occlusion (PICSO). Recently, we reported acute molecular signs and signals of PICSO activating regulatory miRNA and inducing cell proliferation mimicking cardiac development in adult failing hearts. According to a previously formulated hypothesis, 'embryonic recall', this study aimed to define molecular signals involved in endogenous heart repair during PICSO and study their relation to patient survival.
METHODS AND RESULTS
We previously reported a study on the acute molecular effects of PICSO in an observational non-randomized study. Eight out of the thirty-two patients with advanced heart failure undergoing cardiac resynchronization therapy (CRT) were treated with PICSO. Survival was monitored over 10 years, and coronary sinus blood samples were collected during intervention before and after 20 min and tested for miRNA signalling and proliferation when co-cultured with cardiomyocytes. A numerically lower death rate post-CRT and PICSO as compared with control CRT only, and a non-significant reduction in all-cause mortality risk of 42% was observed (37.5% vs. 54.0%, relative risk = 0.58, 95% confidence interval: 0.17-2.05; P = 0.402). Four miRNAs involved in cell cycle, proliferation, morphogenesis, embryonic development, and apoptosis significantly increased concomitantly in survivors and PICSO compared with a decrease in non-survivors (hsa-miR Let7b, P < 0.01; hsa-miR- 421, P < 0.006; hsa-miR 363-3p, P < 0.03 and hsa-miR 19b-3p P < 0.01). In contrast, three miRNAs involved in proliferation and survival, determining cell fate, and recycling endosomes decreased in survivors and PICSO (hsa miR 101-3p, P < 0.03; hsa-miR 25-3p, P < 002; hsa-miR 30d-5p P < 0.04). In vitro cellular proliferation increased in survivors and lowered in non-survivors showing a pattern distinction, discriminating longevity according to up to 10-year survival in heart failure patients.
CONCLUSIONS
This study proposes that generating regenerative signals observed during PICSO intervention relate to patient outcomes. Morphogenetic pathways induced by periods of flow reversal in cardiac veins in a domino-like pattern transform embryonic into regenerative signals. Studies supporting the conversion of mechanochemical signals into regenerative molecules during PICSO are warranted to substantiate predictive power on patient longevity, opening new therapeutic avenues in otherwise untreatable heart failure.
Topics: Adult; Animals; Humans; Myocytes, Cardiac; Circulating MicroRNA; Mechanotransduction, Cellular; MicroRNAs; Heart Failure; Cell Proliferation; Mammals
PubMed: 37752740
DOI: 10.1002/ehf2.14516 -
Frontiers in Immunology 2024
Topics: Humans; Apoptosis; Necrosis; Regulated Cell Death; Inflammation
PubMed: 38318182
DOI: 10.3389/fimmu.2024.1367215 -
Pitavastatin induces autophagy-dependent ferroptosis in MDA-MB-231 cells via the mevalonate pathway.Heliyon Mar 2024Triple-negative breast cancer (TNBC) is more prone to recurrence and metastasis relative to other subtypes of breast cancer, leading to an extremely poor prognosis. The...
Triple-negative breast cancer (TNBC) is more prone to recurrence and metastasis relative to other subtypes of breast cancer, leading to an extremely poor prognosis. The increasing potential chemoresistance of TNBC patients is mainly due to that tumor cells escape from apoptosis. In recent years, statins have demonstrated extensive anti-tumor effects. It is worth noting that statins have more effective anti-tumor effects on TNBC cells and drug-resistant breast cancer cells. Therefore, this study examines the superior cytotoxic effects of statins on TNBC cell lines and further explores their potential therapeutic mechanisms. We detected different cell phenotypes and found that statins significantly reduced the cell viability of TNBC cells. Specifically, pitavastatin showed an obvious induction in cell death, cell cycle arrest and oxidative stress in TNBC MDA-MB-231 cells. The reversal effect of iron chelator desferrioxamine (DFO) on the morphological and molecular biological changes induced by pitavastatin has revealed a new mode of cell death induced by pitavastatin: ferroptosis. This ferroptotic effect was strengthened by the decreased expression of glutathione peroxidase 4 (GPx4) as well as newly discovered ferroptosis suppressor protein 1 (FSP1). The data showed that ferroptotic death of MDA-MB-231 cells is autophagy-dependent and mediated by the mevalonate pathway. Finally, we found that therapeutic oral doses of statins can inhibit the growth of transplanted tumors, which establishes statins as a potential treatment for TNBC patients. In conclusion, we found pitavastatin could induce autophagy-dependent ferroptosis in TNBC cells via the mevalonate pathway which may become a potential adjuvant treatment option for TNBC patients.
PubMed: 38444467
DOI: 10.1016/j.heliyon.2024.e27084 -
Developmental Cell Apr 2024Proteotoxic stress drives numerous degenerative diseases. Cells initially adapt to misfolded proteins by activating the unfolded protein response (UPR), including...
Proteotoxic stress drives numerous degenerative diseases. Cells initially adapt to misfolded proteins by activating the unfolded protein response (UPR), including endoplasmic-reticulum-associated protein degradation (ERAD). However, persistent stress triggers apoptosis. Enhancing ERAD is a promising therapeutic approach for protein misfolding diseases. The ER-localized Zn transporter ZIP7 is conserved from plants to humans and required for intestinal self-renewal, Notch signaling, cell motility, and survival. However, a unifying mechanism underlying these diverse phenotypes was unknown. In studying Drosophila border cell migration, we discovered that ZIP7-mediated Zn transport enhances the obligatory deubiquitination of proteins by the Rpn11 Zn metalloproteinase in the proteasome lid. In human cells, ZIP7 and Zn are limiting for deubiquitination. In a Drosophila model of neurodegeneration caused by misfolded rhodopsin (Rh1), ZIP7 overexpression degrades misfolded Rh1 and rescues photoreceptor viability and fly vision. Thus, ZIP7-mediated Zn transport is a previously unknown, rate-limiting step for ERAD in vivo with therapeutic potential in protein misfolding diseases.
PubMed: 38670102
DOI: 10.1016/j.devcel.2024.04.003 -
Current Issues in Molecular Biology May 2024The many limitations of implementing anticancer strategies under the term "precision oncology" have been extensively discussed. While some authors propose promising... (Review)
Review
The many limitations of implementing anticancer strategies under the term "precision oncology" have been extensively discussed. While some authors propose promising future directions, others are less optimistic and use phrases such as illusion, hype, and false hypotheses. The reality is revealed by practicing clinicians and cancer patients in various online publications, one of which has stated that "in the quest for the next cancer cure, few researchers bother to look back at the graveyard of failed medicines to figure out what went wrong". The message is clear: Novel therapeutic strategies with catchy names (e.g., synthetic "lethality") have not fulfilled their promises despite decades of extensive research and clinical trials. The main purpose of this review is to discuss key challenges in solid tumor therapy that surprisingly continue to be overlooked by the Nomenclature Committee on Cell Death (NCCD) and numerous other authors. These challenges include: The impact of chemotherapy-induced genome chaos (e.g., multinucleation) on resistance and relapse, oncogenic function of caspase 3, cancer cell anastasis (recovery from late stages of apoptosis), and pitfalls of ubiquitously used preclinical chemosensitivity assays (e.g., cell "viability" and tumor growth delay studies in live animals) that score such pro-survival responses as "lethal" events. The studies outlined herein underscore the need for new directions in the management of solid tumors.
PubMed: 38920994
DOI: 10.3390/cimb46060322