Cell Death & Disease最新文献

Lung adenocarcinoma (LUAD) is a common malignant tumor in the lung that seriously endangers the health of people worldwide. The neutrophil-associated inflammatory microenvironment contributes to the activation of tumor cells. In this study, we report a role of tumor-associated neutrophils (TANs) promote tumor progression of LUAD by crosstalk between neutrophils and tumor cells. Mechanistically, in co-culture with tumor cells, downregulation of TPM2 on tumor cells increases neutrophil elastase (ELANE) levels in neutrophils regulated by p38/ MAPK signaling activation, and ELANE promotes tumor cell progression through the Hippo pathway. Furthermore, downregulation of TPM2 activates ELANE of neutrophils to facilitate ERK1/2 activation, thus enhancing IL1β and IL8 secretion for chemoattraction of more neutrophils to tumor microenvironment. The new studies identify an accomplice role for the interaction between TPM2 and ELANE in promoting LUAD progression and provide potential strategies in the prevention and/or treatment of LUAD and other cancers.

Cholesterol plays a crucial role in tumor metabolism. Studies have shown that the serum cholesterol level of multiple myeloma (MM) patients significantly decreases, probably owing to the augmented uptake by MM cells. Despite its significance for MM, research on its metabolism within MM is limited. Our analysis of clinical data from 703 newly diagnosed MM patients revealed that low serum cholesterol is associated with poor prognosis, and it stems from the elevated cholesterol consumption by MM cells. By exploring the transcriptome and single-cell RNA-seq data of patients with different cholesterol levels in our center, we identified LRP8 as a key regulator of cholesterol metabolism in MM, which is closely related to prognosis and disease stages. We verified the oncogenic role of LRP8 in vitro and in vivo. Knockdown of LRP8 can facilitate apoptosis and cell cycle arrest in MM cells. Meanwhile, we employed mouse xenograft tumor model to replicate the phenomenon that MM cells with high LRP8 expression consume cholesterol, causing low serum cholesterol. Mechanistically, high LRP8 expression enhances cholesterol utilization and uptake by MM cells; LRP8 inhibition reduces cholesterol absorption, further weakening the activity of the cholesterol-dependent mTORC1 pathway in MM cells and inducing apoptosis. Concurrently, it triggers an upregulation of protective autophagy. Further suppression of autophagy can lead to extensive apoptosis of MM cells. Our study reveals that LRP8 regulates cholesterol metabolism in MM cells and influences the processes of cell apoptosis and autophagy through metabolic-related pathways. LRP8 holds potential as a therapeutic target for MM.

The tumor microenvironment (TME) of gliomas comprises glioma cells and surrounding cells, such as astrocytes, macrophages, T cells, and neurons. In the TME, glioma cells can activate normal human astrocytes (NHAs) through the secretion of exosomes and the activation of astrocytes can further improve the progression of glioma, leading to a poor prognosis for patients. However, the molecular mechanisms underlying NHAs activation by gliomas remain largely unknown. It this study, glioma-derived exosomes (GDEs) play an important role in the modulation of autophagy and activation of NHAs. Compared with normoxic GDEs, hypoxic glioma-derived exosomes (H-GDEs) further improved autophagy and activation of astrocytes, which strongly promoted the progression of glioma cells. In an miRNA array between two types of exosomes from gliomas, miR-423-3p was highly expressed in H-GDEs and played an important role in autophagy, resulting in the activation of NHAs. The mechanism by which hypoxic glioma cells react with NHAs to create an immunosuppressive microenvironment was identified and 15d-PGJ2 was established as an effective inhibitor of miR-423-3p to suppress NHAs activation. These findings provide new insights into the diagnosis and treatment of gliomas by targeting autophagy and miR-423-3p expression.

Duchenne muscular dystrophy (DMD) is a devastating genetic disorder, whose management is still a major challenge, despite progress in genetic and pharmacological disease-modifying treatments have been made. Mitochondrial dysfunctions contribute to DMD, however, there are no effective mitochondrial therapies for DMD. SIRT1 is a NAD⁺-dependent deacetylase that controls several key processes and whose impairment is involved in determining mitochondrial dysfunction in DMD. In addition to well-known resveratrol, other potent selective activators of SIRT1 exist, with better pharmacokinetics properties and a safer profile. Among these, SRT2104 is the most promising and advanced in clinical studies. Here we unveil the beneficial effects of SRT2104 in flies, mice, and patient-derived myoblasts as different models of DMD, demonstrating an anti-inflammatory, anti-fibrotic, and pro-regenerative action of the drug. We elucidate, by molecular dynamics simulations, that a conformational selection mechanism is responsible for the activation of SIRT1. Further, the impact of SRT2104 in reshaping muscle proteome and acetylome profiles has been investigated, highlighting effects that mimic those induced by exercise. Overall, our data suggest SRT2104 as a possible therapeutic candidate to successfully counteract DMD progression.

Glioma is a highly aggressive brain tumor with limited treatment success due to its resistance to conventional therapies. Sirtuin 5 (SIRT5) has emerged as a promising target for cancer therapy, though it exhibits dual roles in different cancer types. In this study, we investigate the role of SIRT5 in glioma and its corresponding mechanisms. Our findings demonstrate that SIRT5 expression is elevated in glioma cells both in vitro and in vivo. SIRT5 knockdown significantly reduced glioma cell proliferation and enhanced sensitivity to ferroptosis. Proteomic and metabolomic analyses identifies branched-chain amino acid (BCAA) metabolism as a key downstream pathway regulated by SIRT5 through branched-chain aminotransferase 1 (BCAT1). Specifically, SIRT5-mediated desuccinylation of BCAT1 at K39 inhibits its interaction with the E3 ligase CHIP, thereby preventing BCAT1 degradation via the ubiquitin-proteasome system. Moreover, BCAT1 overexpression reverses the proliferation inhibition and ferroptosis sensitivity observed in SIRT5-knockdown cells. Clinically, we reveal a positive correlation between SIRT5 and BCAT1 levels in glioma samples, with higher expression levels predicting more advanced glioma grades and poorer clinical outcomes. Collectively, this study highlights the critical role of SIRT5 in promoting glioma progression via metabolic regulation and ferroptosis insensitivity, offering a potential therapeutic target for glioma treatment.

Radiotherapy, as a vital means of esophageal cancer treatment, has benefited countless cancer patients, but owing to the occurrence of radio-resistance, its therapeutic efficiency has been dramatically mitigated. Discovering key biomarkers governing radio-tolerance in esophageal cancer and revealing their inherent molecular mechanisms will be of great significance for clinical cancer treatment. Here, we have found roundabout guidance receptor 1 (ROBO1) was significantly upregulated in esophageal cancerous tissues and showed enhanced expression with the development of cancer staging. Cellular experiments demonstrated ROBO1 directly interacted with eukaryotic translation initiation factor 3A (eIF3A) and accelerated its degradation in esophageal cancer cells after irradiation treatment. Mass spectrum analysis further revealed that in response to irradiation, ROBO1, eIF3A and G3BP2 (Ras GTPase-activating protein-binding protein 2) formed a hetero-complex and triggered lysosomes-mediated protein degradation. Knocking down of G3BP2 abrogated the influence of ROBO1 on eIF3A instability. Besides, ROBO1-mediated eIF3A degradation interrupted P53 translation process which in turn provoked downstream mTOR signaling and increased DNA repair associated genes expressions, resulting in radio-resistance enhancement in cancer cells. In conclusion, our findings revealed a novel role of eIF3A in modulating P53/mTOR signaling activity and provided a drug candidate (ROBO1) for overcoming radio-resistance in esophageal cancer.

Neoadjuvant radiotherapy is the standard treatment for locally advanced rectal cancer, but resistance to this therapy remains a significant clinical challenge. Understanding the molecular mechanisms of radioresistance and developing strategies to enhance radiosensitivity are crucial for improving treatment outcomes. This study investigated the role of PRKCSH in colorectal cancer radioresistance and its underlying mechanisms. Our results demonstrate that PRKCSH is upregulated in colorectal cancer cells following ionizing radiation. Inhibiting PRKCSH sensitized these cells to radiation by reducing clonogenic survival, promoting apoptosis, and impairing DNA damage repair. Mechanistically, PRKCSH inhibition reduced p53 ubiquitination and degradation by activating the ER stress IRE1α/XBP1s pathway after radiation exposure, which enhanced DNA repair and contributed to radioresistance. In preclinical CRC models, PRKCSH depletion suppressed tumor growth and increased radiosensitivity. Similarly, in patient-derived organoid models, PRKCSH knockdown reduced organoid growth post-radiotherapy. In rectal cancer patients receiving neoadjuvant radiotherapy, higher PRKCSH expression in post-treatment samples correlated with reduced tumor regression. These findings suggest that targeting PRKCSH diminishes radioresistance by impairing DNA repair through the modulation of ER stress. Furthermore, PRKCSH expression may serve as a biomarker for evaluating radiotherapy efficacy and clinical outcomes in rectal cancer patients undergoing neoadjuvant therapy.

Protein tyrosine phosphatase mitochondrial 1 (PTPMT1), is a member of the protein tyrosine phosphatase superfamily localized on the mitochondrial inner membrane, and regulates the biosynthesis of cardiolipin. Given the important position of PTPMT1 in mitochondrial function and metabolism, pharmacological targeting of PTPMT1 is considered a promising manner in disease treatments. In this study, we mainly investigated the role of PTPMT1 in hepatocellular carcinoma (HCC) ferroptosis, a new type of cell death accompanied by significant iron accumulation and lipid peroxidation. Herein, the pharmacological inhibition of PTPMT1 was induced by alexidine dihydrochloride (AD, a dibiguanide compound). Human HCC cell lines with PTPMT1 knockout and PTPMT1 overexpression were established using CRISPR/Cas9 and lentiviral transduction methods, respectively. The position of PTPMT1 in regulating HCC ferroptosis was evaluated in vitro and in vivo. Our results indicated that pharmacological inhibition of PTPMT1, facilitated by AD treatment, heightens the susceptibility of HCC to cystine deprivation-ferroptosis, and AD treatment promoted the conversion from ferritin-bound Fe³⁺ to free Fe²⁺, which contributed to the labile iron pool in cytoplasm. Meanwhile, pharmacological inhibition of PTPMT1 also induced the formation of both swollen mitochondria and donut mitochondria, and enhanced the metabolism process form succinate to fumarate in mitochondrial tricarboxylic acid (TCA) cycle, which increased the sensitivity of HCC cells to cystine deprivation-induced ferroptosis. In total, our work reveals the close association of PTPMT1 with cysteine deprivation-induced ferroptosis, providing a novel insight into chemotherapy strategies against human HCC.