Apoptosis最新文献

Background

The upregulated expression of sterol regulatory element-binding protein 2 (SREBP2) has been observed in multiple types of malignant cancers. Ferroptosis is a form of cell death that is iron-dependent and driven by the accumulation of lipid peroxides. It has recently garnered considerable attention in Colorectal cancer (CRC) research. This study aims to investigate the role of SREBP2 in CRC ferroptosis resistance and the underlying molecular mechanisms.

Methods

SREBP2 expression was assessed in CRC. Functional assays were conducted in HT29 and RKO cells following SREBP2 knockdown or treatment with Betulin, the SREBP2 inhibitor. RNA-seq was used to screen the potential downstream targets of SREBP2. Mechanistically, ferroptosis-related markers and rescue assays revealed the relation between SREBP2 and CRC ferroptosis resistance mediated by GPX4 expression regulation. Furthermore, ChIP and luciferase assays were used to confirm the upstream that regulates SREBP2 expression. Finally, subcutaneous tumorigenesis model was employed to evaluate the therapeutic potential of targeting SREBP2 in CRC.

Results

The upregulated SREBP2 expression in CRC drives the proliferation, migration, and invasion of CRC cells. Mechanistically, SREBP2 directly increases GPX4 transcription, thereby reducing the sensitivity of CRC to ferroptosis and facilitating CRC progression. Additionally, β-catenin was identified as an upstream regulator of SREBP2. Inhibition of SREBP2 sensitizes CRC cells to ferroptosis and suppresses tumor growth.

Conclusion

SREBP2 enhances ferroptosis resistance in CRC by upregulating GPX4, thereby contributing to tumor progression. Our findings highlight SREBP2 as a potential therapeutic target and provide a rationale for the development of SREBP2-targeted strategies in colorectal cancer.

Hepatocellular carcinoma (HCC) remains the most common primary liver cancer, with a high incidence and mortality rate. Remarkable progress has been made in cancer treatment in recent years; however, most patients with HCC still receive limited benefits from current treatment options. Therefore, there is an urgent need to explore novel and effective therapeutic strategies. Here, a novel combination therapy consisting of the calcineurin inhibitor cyclosporine A (CsA) and the flavone-naphthalimide-polyamine derivative 6c was identified. The combination of CsA and 6c inhibited cell viability and colony formation and induced GSDME-dependent pyroptosis. Mechanistically, RNA sequencing revealed that CsA and 6c synergistically activated the RIG-I-like receptor (RLR) signaling pathway. Moreover, the combination of CsA and 6c promoted RIG-I and MDA5 expression, TBK1 and IRF3 phosphorylation, and downstream target gene expression. RIG-I deletion attenuated the combination treatment-induced inhibition of cell growth, pyroptosis, and expression of IFN-stimulated genes (ISGs). Furthermore, combination treatment induced the downregulation of LDHA expression, leading to increased reactive oxygen species (ROS) generation. LDHA overexpression and ROS removal reversed the inhibitory effect of the combination treatment on HCC. Finally, combination of CsA and 6c suppressed tumor growth and pulmonary metastasis in vivo. Overall, our study suggests a novel synergistic treatment combination with a comprehensive mechanistic exploration, demonstrating that it is a promising strategy for HCC treatment via targeting RIG-I-like receptor signaling.

In recent years, the application of estrogen in skin health and disease prevention has garnered significant attention, and it is now widely involved in the intervention and study of various skin conditions. Experimental evidence shows that estrogen has profound effects on the structure and function of the skin, including the synthesis of collagen and elastin, regulation of skin pigmentation, and control of sebum secretion. This review systematically summarizes the multifaceted effects of estrogen on skin health and diseases, with a focus on the mechanisms by which different types of estrogen influence skin aging, pigmentation, and other related issues. Additionally, we explore how estrogen exerts its effects on the skin through various signaling pathways, such as estrogen receptor-mediated signaling, phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), and mitogen-activated protein kinase (MAPK) pathways. Through a comprehensive analysis of the existing studies, this review aims to provide a deeper understanding of the complex interactions between estrogen and the skin, offering a comprehensive perspective on estrogen’s role in skin physiology and pathology.

Graphical abstract

A Ovarian production and receptor-mediated systemic effects; B Modulation of cutaneous pathologies; C Nuclear (nER) and membrane (mER) receptor pathways; D Novel skin-lightening agents derived from plant estrogens; E Natural, phyto-, synthetic, and xenoestrogens)

Nucleolar stress has emerged as a critical regulatory mechanism linking ribosome biogenesis defects to apoptotic cell death in various pathological conditions. Fibrillarin (FBL), the catalytic component of box C/D small nucleolar ribonucleoproteins, participates in multiple forms of programmed cell death through both p53-dependent and p53-independent pathways across diverse disease contexts including cancer and neurodegeneration. In malignancies including breast cancer, colorectal cancer, and hepatocellular carcinoma, FBL overexpression promotes apoptosis resistance, whereas in Alzheimer’s disease and ALS/FTD, FBL dysfunction contributes to pathological neuronal death. Dysregulation of FBL can lead to excessive apoptosis or apoptosis resistance depending on cellular context and disease state. Various cellular stressors trigger aberrant FBL function, disrupting rRNA processing and ribosome assembly, which then activates nucleolar stress responses that culminate in cell death through ribosomal protein-MDM2-p53 axis activation or selective translational control of survival factors in a context-dependent manner. Therefore, targeting FBL-mediated apoptotic pathways is considered an important avenue for the treatment of various cancers and neurodegenerative diseases. In this review, we summarize the major and recent findings focusing on the mechanisms of FBL-regulated apoptosis in disease pathogenesis and provide a systematic overview of current therapeutic strategies targeting nucleolar stress pathways, including RNA polymerase I inhibitors and precision medicine approaches based on p53 status, which may provide important therapeutic targets that merit further investigation.

Colorectal cancer (CRC) ranks among the most prevalent and lethal malignancies globally, with Cetuximab (CTx) resistance being a significant hurdle in its treatment. To uncover the underlying mechanisms, this study recruited 27 metastatic CRC patients undergoing CTx-based therapy and categorized them into responder and non-responder groups. In addition to measuring succinate levels in serum and tumor tissues and evaluating M2 macrophage infiltration in patients, a series of in vitro and in vivo experiments were conducted. In vitro, HT29 and Caco2 cells were treated with CTx and succinate under different conditions, including monoculture and co-culture with macrophages. The results indicated that succinate enhanced CRC cells’ resistance to CTx specifically in the presence of macrophages by promoting M2 macrophage polarization. This effect was found to be mediated by succinate receptor 1 (SUCNR1), as demonstrated by experiments involving SUCNR1 knockdown. In vivo, the addition of succinate promoted tumor growth and weakened the inhibitory effect of CTx through macrophages. Further exploration revealed that succinate-induced polarized tumor-associated macrophages secreted IL-6, which played a crucial role in conferring CTx resistance. Overall, this study uncovers that tumor-secreted succinate confers CTx resistance in CRC by activating SUCNR1, thereby driving M2 macrophage polarization. These findings offer novel insights into the mechanisms of CRC resistance and identify potential therapeutic targets within the tumor microenvironment, which could potentially lead to the development of more effective treatment strategies for CRC patients.

Traditional chemotherapeutic agents are indispensable in cancer treatment. However, their therapeutic efficacy is frequently constrained by associated toxicities and adverse effects. Among these adverse effects, cardiotoxicity has emerged as a major clinical concern due to the increasing incidence. Emerging evidence suggests that oxidative stress, programmed cell death pathways, oxidative stress, and inflammatory cascades predominantly mediate the pathogenesis of cardiotoxicity induced by chemotherapeutic agents. Current strategies for monitoring and prevention rely on potential biomarkers, including markers of myocardial injury (e.g., troponins and natriuretic peptides), inflammatory mediators (e.g., myeloperoxidase, interleukin-6, C-reactive protein, and tumor necrosis factor-alpha), and exosomal contents (e.g., microRNAs, proteins, and metabolites). Clinical trials and case reports have demonstrated that patients with chemotherapy-induced cardiotoxicity may benefit from therapeutic interventions such as angiotensin-converting enzyme inhibitors, dexrazoxane, and β-blockers. However, limitations associated with these potential biomarkers and therapeutic agents warrant further discussion because of the lack of solid evidence from large-scale, prospective clinical studies. In summary, further research is imperative to enhance the understanding, monitoring, and therapeutic management of cardiotoxicity associated with traditional chemotherapeutic agents.

This study aimed to investigate the roles of ANXA7 and its upstream regulator RNF168 in Crohn’s disease (CD) progression, focusing on their interaction with inflammation and intestinal mucosal barrier disruption. Colon tissues from CD patients, including inflamed and uninflamed tissues, were analyzed to assess ANXA7 expression. The biological functions of ANXA7 were studied in vitro using LPS/ATP-stimulated NCM460 cells, employing ANXA7 knockdown and overexpression experiments. Protein–protein interactions were examined using co-immunoprecipitation (Co-IP) and mass spectrometry. The regulatory role of RNF168 in ANXA7 degradation was explored through Co-IP and ubiquitination assays. The effects of RNF168 and ANXA7 on autophagy and NLRP3 inflammasome-induced pyroptosis were assessed. In vivo experiments were conducted using IL-10 knockout (KO) mice, RNF168^{flox/flox; Villin−Cre} mice with TNBS-induced colitis, and organoids to investigate the therapeutic potential of RNF168 and ANXA7 manipulation. ANXA7 expression was significantly reduced in inflamed tissues and correlated with CD-related inflammatory markers. RNF168 promoted the ubiquitination and degradation of ANXA7, thereby suppressing autophagy and inducing NLRP3 inflammasome-mediated pyroptosis. The in vitro and in vivo biological functions of sh-RNF168 were rescued by sh-ANXA7. ELK1 was identified as a key transcription factor regulating RNF168 expression, linking transcriptional regulation with inflammation and disease progression. Our findings suggest a mechanistic model where ELK1 upregulates RNF168, leading to ANXA7 degradation, suppression of autophagy, and enhanced pyroptosis, thereby promoting CD progression and intestinal barrier disruption. Targeting the RNF168-ANXA7 axis offers a potential therapeutic strategy for CD.

S-palmitoylation, a reversible lipid post-translational modification, plays a dynamically regulatory role in cell death signaling pathways by modulating protein-membrane affinity, subcellular localization, and functional interactions. Emerging evidence has linked dysregulated S-palmitoylation to various pathologies including cancer and neurodegenerative disorders. Recently, several advances highlight its novel involvement in ferroptosis, an iron-dependent programmed cell death mechanism characterized with lipid peroxidation and iron accumulation. However, the precise regulatory impact of S-palmitoylation on ferroptosis remains to be fully elucidated. Notably, certain key regulators of ferroptosis undergo degradation through autophagy pathways, indicating an intricate crosstalk between ferroptosis and autophagy. Herein, the current review summarized the molecular mechanisms and physiological functions of ferroptosis and S-palmitoylation, with a particular focus on the pivotal role of palmitoylated ferroptosis-related regulators. Importantly, the interaction between autophagy and ferroptosis, especially the S-palmitoylated proteins that modulate both processes were discussed as well. This review provides a new perspective for the accurate regulation of ferroptosis by modulating S-palmitoylation, thus may improve the overall prognosis through optimizing the treatment regimens or via enhancing the efficacy of existing therapies.

Extracellular matrix (ECM) detachment is crucial for metastasis in cancer cells. During tumorigenesis, a programmed cell death occurs to clear off the ECM detached cancer cells in the circulatory system; this phenomenon is referred to as anoikis. Metastatic cancer cells can evade anoikis by regulating mechanisms such as cell adhesion, cell growth, oxidative stress, cancer stemness, hypoxia and metabolic reprogramming. Studies have shown that RNA modifications regulate multiple cancer mechanisms; however, the role of RNA modifications in anoikis resistant is not established yet. Therefore, in this study, we assessed the role of N6-methyladenosine (m6A) modification of mRNAs in anoikis resistant conditions. First, we cultured cancer cells in low adhesive plates for six (6) days followed by quantitative real-time PCR (qRT-PCR) of major m6A regulators and quantification of the global m6A levels in detached versus attached cancer cells. We also assessed cell proliferation in detached cancer cells using STM2457, a potent and specific METTL3 inhibitor. Our results showed a significant (p < 0.05) increase in METTL3 expression and activity in anoikis resistant cancer cells. Furthermore, we observed an elevation in global m6A levels on mRNAs. Treatment of anoikis resistant cancer cells with STM2457 caused reduction in spheroid size, induction of apoptosis, and cell cycle arrest which were correlated with a decrease in global m6A levels. Conclusively, our findings reveal that METTL3-dependent m6A methylation sustains the survival and proliferation of anoikis-resistant cancer cells, highlighting an epitranscriptomic mechanism underlying metastatic fitness.

Copper is essential for cellular homeostasis and can induce cuproptosis, a novel form of cell death. However, its effect on cancer progression, specifically through the regulation of epithelial-mesenchymal transition (EMT)—a primary driver of metastasis and treatment resistance in human cancers—remains unclear. This study assessed the dual role of copper in colorectal cancer cells, focusing on the polo-like kinase 1-forkhead box O3a-beta catenin (PLK1-FOXO3a-β-catenin) signaling pathway. Treatment with CuCl₂ (hereby referred to as Cu) alone facilitated EMT in SW480 and LoVo cells by upregulating PLK1 and downregulating FOXO3a that enhanced β-catenin activity without inducing cell death. In contrast, co-treatment with Cu and copper ionophore elesclomol (Cu-ES) triggered cuproptosis, a unique copper-dependent form of cell death, accompanied by mitochondrial dysfunction, dihydrolipoamide S-acetyltransferase aggregation, and ATP depletion. Specifically, Cu-ES treatment suppressed EMT by reducing PLK1 and activating FOXO3a that suppressed β-catenin-mediated transcription. Additionally, while Cu treatment alone had minimal effect on FOXO3a nuclear localization, Cu-ES treatment significantly enhanced FOXO3a nuclear translocation and its interaction with β-catenin, resulting in EMT gene repression. The PLK1 inhibitor BI-2536 recapitulated the effects of Cu-ES and exhibited synergistic activity when combined with Cu-ES, enhancing both cell death and EMT suppression. These findings highlight a novel regulatory mechanism of EMT through copper signaling and support copper-based combination therapies as a promising approach to simultaneously inhibit tumor growth and metastasis in colorectal cancer.