Cell Death Discovery最新文献

Cancer is among the leading causes of death related diseases worldwide, and lung cancer has the highest mortality rate in the world. Transcription factors (TFs) constitute a class of structurally and functionally intricate proteins. Aberrant expression or functional deficiencies of transcription factors may give rise to abnormal gene expression, contributing to various diseases, including tumours. In this study, we propose to elucidate the potential role and mechanism of TFAP2A in NSCLC. We found that TFAP2A levels were significantly greater in tumour tissues than para-tumour tissues, and high expression of TFAP2A was associated with poor prognosis in NSCLC patients. Additionally, TFAP2A overexpression promoted NSCLC progression both in vivo and in vitro. Mechanistically, ESR2 is a potential target regulated by TFAP2A and that TFAP2A can bind to the promoter region of ESR2. Furthermore, the overexpression of both TFAP2A and ESR2 in NSCLC cells was associated with the overactivation of MAPK signalling, and the combination of PHTPP and osimertinib had a synergistic effect on suppressing tumour growth.

The ASPP (apoptosis-stimulating protein of p53) family of proteins is involved in many cellular interactions and is starting to emerge as a major scaffolding hub for numerous proteins involved in cancer biology, inflammation and cellular integrity. It consists of the three members ASPP1, ASPP2 and iASPP which are best known for modulating the apoptotic function of p53, thereby directing cell fate decision. Germline mutations in iASPP have been shown to cause cardiocutaneous syndromes, a combination of heart and skin defects usually leading to death before the age of five. Mutations in iASPP causing these syndromes do not cluster in hot spots but are distributed throughout the protein. To understand the molecular mechanism(s) of how mutations in iASPP cause the development of cardiocutaneous syndromes we analysed the stability and solubility of iASPP mutants, characterized their interaction with chaperones and investigated their influence on NF-ĸB activity. Here we show that three different mechanisms are responsible for loss of function of iASPP: loss of the complete C-terminal domain, mutations resulting in increased auto-inhibition and aggregation due to destabilization of the C-terminal domain. In contrast to these germline mutations causing cardiocutaneous syndromes, missense mutations found in cancer do not result in aggregation.

Radiotherapy remains a key treatment modality for both primary and metastatic brain tumors. Significant technological advances in precision radiotherapy, such as stereotactic radiosurgery and intensity-modulated radiotherapy, have contributed to improved clinical outcomes. Notably, however, molecular genetics is not yet widely used to inform brain radiotherapy treatment. By comparison, genetic testing now plays a significant role in guiding targeted therapies and immunotherapies, particularly for brain metastases (BM) of lung cancer, breast cancer, and melanoma. Given increasing evidence of the importance of tumor genetics to radiation response, this may represent a currently under-utilized means of enhancing treatment outcomes. In addition, recent studies have shown potentially actionable mutations in BM which are not present in the primary tumor. Overall, this suggests that further investigation into the pathways mediating radiation response variability is warranted. Here, we provide an overview of key mechanisms implicated in BM radiation resistance, including intrinsic and acquired resistance and intratumoral heterogeneity. We then discuss advances in tumor sampling methods, such as a collection of cell-free DNA and RNA, as well as progress in genomic analysis. We further consider how these tools may be applied to provide personalized radiotherapy for BM, including patient stratification, detection of radiotoxicity, and use of radiosensitization agents. In addition, we describe recent developments in preclinical models of BM and consider their relevance to investigating radiation response. Given the increase in clinical trials evaluating the combination of radiotherapy and targeted therapies, as well as the rising incidence of BM, it is essential to develop genomically informed approaches to enhance radiation response.

Efferocytosis, the clearance of apoptotic cells, is a critical process that maintains tissue homeostasis and immune regulation. Defective efferocytosis is linked to the development of chronic inflammatory conditions, including atherosclerosis, neurological disorders, and autoimmune diseases. Moreover, the interplay between autophagy and efferocytosis is crucial for inflammation control, as autophagy enhances the ability of phagocytic cells. Efficient efferocytosis, in turn, regulates autophagic pathways, fostering a balanced cellular environment. Dysregulation of this balance can contribute to the pathogenesis of various disorders. Phytochemicals, bioactive compounds found in plants, have emerged as promising therapeutic agents owing to their diverse pharmacological properties, including antioxidant, anti-inflammatory, and immunomodulatory effects. This review aims to highlight the pivotal role of phytochemicals in enhancing efferocytosis and autophagy and explore their potential in the prevention and treatment of related disorders. This study examines how phytochemicals influence key aspects of efferocytosis, including phagocytic cell activation, macrophage polarization, and autophagy induction. The therapeutic potential of phytochemicals in atherosclerosis and neurological diseases is highlighted, emphasizing their ability to enhance efferocytosis and autophagy and reduce inflammation. This review also discusses innovative approaches, such as nanoformulations and combination therapies to improve the targeting and bioavailability of phytochemicals. Ultimately, this study inspires further research and clinical applications in phytochemical-mediated efferocytosis enhancement for managing chronic inflammatory and autoimmune conditions.

The RNA-binding protein HuR regulates various cellular processes, such as proliferation, differentiation, and cell fate. Moreover, recent studies have shown that HuR modulates the expression of factors important for tumor growth and progression. Despite its prominent role in tumorigenesis, until recently, there have been no reported mutations in HuR that have been associated to cancer. Here, we show that a HuR mutation, HuR-V225I, previously identified in a patient with Adult T-cell Leukemia/Lymphoma, interferes with the pro-apoptotic function of HuR. In response to apoptosis, HuR translocates to the cytoplasm and is cleaved in a caspase-dependent manner. In cervical cancer cells, neuroblastoma cells, and T-lymphocytes, we observed a decrease in cleavage of the HuR-V225I mutant under apoptotic conditions. This effect was shown to be mediated by the nuclear retention of HuR-V225I. Finally, expression of the HuR-V225I mutant decreases the cell's response to apoptotic stimuli through the increased expression of mRNAs encoding anti-apoptotic factors, such as XIAP and BCL-2. Therefore, our data establishes that the absence of HuR cytoplasmic translocation and cleavage promotes cell viability, and that acquiring this mutation during tumorigenesis may thus reduce the efficacy of cancer therapy.

Hepatocellular carcinoma (HCC) is one of the most frequent solid tumors worldwide. According to the Global Cancer Statistics 2020, liver cancer remains the third cause of cancer death globally. Despite significant advances in systemic therapy, HCC still has one of the worst prognoses due to its frequent recurrence and metastasis. Previously we found that PDSS2-Del2 (prenyl diphosphate synthase subunit 2 with exon 2 deletion), a novel variant of PDSS2, could promote HCC metastasis and angiogenesis via activating NF-κB. In this study, we elucidate a novel mechanism by which PDSS2-Del2 enhances HCC metastasis. The overexpression of PDSS2-Del2 in HCC cells promotes the ubiquitination and degradation of SKOR1, consequently heightening SMAD3 phosphorylation. Subsequently, the expression and secretion of MST1 (macrophage stimulatory protein 1) are upregulated, resulting in enhanced recruitment of macrophages into tumor tissues where they differentiate into M2-type macrophages. Co-culture with PDSS2-Del2 overexpressed HCC cells activated the PI3K/AKT signaling pathway in macrophages, and more MMP2 and MMP9 were secreted, which facilitated HCC cell dissemination. Our study elucidates a novel molecular mechanism by which PDSS2-Del2 promotes HCC metastasis, which may contribute to the development of effective HCC clinical treatment and prevent tumor metastasis. Furthermore, MST1 could be a potential therapeutic target, and MST1 inhibitors might be integrated into clinical practice for HCC patients with high expression of PDSS2-Del2.

Ribonucleotide reductase M1 (RRM1), the catalytic subunit of ribonucleotide reductase, plays a pivotal role in converting ribonucleotides (NTP) into deoxyribonucleotides (dNTP), essential for DNA replication and repair. Elevated RRM1 expression is associated with various human cancers, correlating with poorer prognosis and reduced overall survival rates. Our previous study found that RRM1 will enter the nucleus to promote DNA damage repair. However, the underlying mechanism remains elusive. Here, we unveil a novel role of RRM1 in promoting homologous recombination (HR) by upregulating the expression of RAD51AP1, a critical HR factor, in an E2F1-dependent manner. We demonstrate that RRM1 interacts with USP11 in the cytoplasm, and the recruitment of RRM1 to LaminB1 induced by ionizing radiation (IR) facilitates the binding of USP11 to the nuclear pore complex (NPC), promoting USP11 entry into the nucleus. Upon nuclear translocation, USP11 binds to E2F1 and inhibits the ubiquitin-mediated degradation of E2F1, thereby enhancing the transcriptional expression of RAD51AP1. Moreover, a specific RRM1 mutant lacking amino acids 731-793, crucial for its interaction with USP11 and recruitment to LaminB1, exhibits a dominant-negative effect on RAD51AP1 expression and HR. Truncations of RRM1 fail to inhibit the ubiquitin-mediated degradation of E2F1 and cannot promote the E2F1-mediated transactivation of RAD51AP1. Lastly, the full length of RRM1, not truncations, enhances tumor cells' sensitivity to IR, underscoring its importance in radiotherapy resistance. Collectively, our results suggest a novel function of RRM1 in promoting HR-mediated DSB repair through positive regulation of RAD51AP1 transcription by direct interaction with USP11 and promoting subsequent USP11-mediated deubiquitination of E2F1. Our findings elucidate a previously unknown mechanism whereby RRM1 promotes HR-mediated DNA repair, presenting a potential therapeutic target for cancer treatment.

Multiple myeloma (MM) is the second common hematological malignancy characterized by the abnormal proliferation of plasma cells. Although advances in the past decades have led to improved outcomes and longer survival, MM remains largely incurable. New targets and targeted therapy may help to achieve better outcomes. Proton exporter NHE1 is highly expressed by tumor cells to maintain pH gradient for their survival and its inhibitor Hexamethylene amiloride (HA) has been demonstrated anti-tumor effect. However, whether HA could inhibit MM remains unknown. In this study, we firstly demonstrated that elevated expression level of NHE1 is associated with poor prognosis of MM. Moreover, the NHE1 inhibitor HA inhibited growth and induced apoptosis effectively in both MM cell lines and primary bone marrow cells from MM patients. Mechanistically, inhibitory effect was achieved partially through TFE3-mediated lysosomal production. With a MM xenograft mouse model, we verified that HA has a significant anti MM effect in vivo. Importantly, HA induced apoptosis of the carfilzomib-resistant MM cells and enhanced the effect of carfilzomib in MM. In summary, we demonstrated that NHE1 inhibitor HA can effectively inhibit MM growth both in vitro and in vivo, providing a new therapeutic strategy for improved outcome of de novo and resistant MM.

Polypeptide N-acetylgalactosaminyltransferase-like protein 5 (GALNTL5) was identified as a pp-GalNAc-T family gene. Nevertheless, GALNTL5 has no glycosyltransferase activity. In mice, Galntl5 expression is restricted to differentiating spermatids, and haploinsufficiency leads to immotile spermatozoa with an aberrant protein composition. Moreover, heterozygotic deletions of human GALNTL5 have been detected in patients diagnosed with asthenozoospermia (low sperm motility). Although these findings indicate that GALNTL5 is a functional molecule essential for mature sperm formation in mammals, the exact function of GALNTL5 in spermiogenesis remains unknown. To clarify this role, we established the mouse spermatocyte cell line GC-2spd(ts), which exhibits drug-inducible GALNTL5 expression. Interestingly, continuous GALNTL5 expression in the resultant cell lines caused apoptosis with cell shrinkage, and GALNTL5 was localized in the endoplasmic reticulum (ER) and was associated with two ER-resident chaperone proteins, calnexin and BiP (GRP78). Calnexin recognized and strongly bound to the N-glycans on GALNTL5 molecules modified in the ER. In contrast, ER-resident BiP likely attached to GALNL5 regardless of its glycosylation. GALNTL5 expression abolished the binding between calnexin and misfolded substrate proteins, indicating that GALNTL5 directly blocks calnexin function. Furthermore, the interaction between GALNTL5 and calnexin decreased the level of BiP protein, and consequently also the expression levels of proteins that are resident in the ER, Golgi apparatus, and cytoplasm. These reduced protein levels were confirmed by loss of calnexin or BiP function in the GC-2spd(ts) cell line using siRNA knockdown. Further, sustained expression of GALNTL5 resulted in cell structure changes, including the position of the cis-Golgi apparatus and alterations in the ER network. These results strongly suggest that GALNTL5 contributes to alteration of the cell structure specific to differentiating spermatids by blocking ER function.

Metastasis-associated in colon cancer-1 (MACC1) was identified as a new player in lung cancer development, and some stemness-related genes can be novel transcriptional targets of MACC1. Cancer stem cells (CSCs) are responsible for sustaining tumorigenesis and plasticity. Both CSCs and non-CSCs are plastic and capable of undergoing phenotypic transition, especially the dedifferentiation of non-CSCs switch to CSC-like cells. However, the precise role of MACC1 during this process is largely unknown. Here, we showed that MACC1 promoted the transition from non-CSC to CSC in lung cancer. We found MACC1 was overexpressed in stemness enriched cells, enhancing the transition from no-CSCs to CSCs, while short-hairpin RNA-mediated Knockdown of MACC1 impaired this process. High-throughput sequencing and tumor specimen analysis revealed that MACC1 was negative correlated with Krüppel-like factor 4 (KLF4) expression level, which acts as a negative stemness regulator in lung cancer. Mechanistically, MACC1 delays the degradation of KLF4 mRNA by repressing the expression of microRNA-25, thereby promoting the KLF4 mRNA stabilization at the post-transcriptional level. Collectively, our findings may facilitate efforts to promote the development of precision targeted therapy for cancer stem cells in lung cancer.