Cell Death Discovery最新文献

Besides the important pathogenic mechanisms of melanoma, including BRAF-driven and immunosuppressive microenvironment, genomic instability and abnormal DNA double-strand breaks (DSB) repair are significant driving forces for its occurrence and development. This suggests investigating novel therapeutic strategies from the synthetic lethality perspective. Poly (ADP-ribose) polymerase 4 (PARP4) is known to be a member of the PARP protein family. The low expression of PARP4 is significantly associated with defective DSB repair markers and poor prognosis in melanoma. Further research revealed that PARP4 plays a role in DSB repair by regulating the non-homologous end joining (NHEJ) pathway through its involvement in Ku80 mono-ADP-ribosylation. Moreover, from a synthetic lethality perspective, PARP4 expression is associated with ATM inhibitor sensitivity. Overall, our study provides new and valuable insights into the function of PARP4 and melanoma pathogenesis and suggests that ATM inhibitor may be a promising therapeutic approach for treating melanoma with low PARP4 expression.

Rhodopsin is the light-activated G protein-coupled receptor that initiates vision in photoreceptor cells of the retina. Numerous mutations in rhodopsin promote receptor misfolding and aggregation, causing autosomal dominant retinitis pigmentosa, a progressive retinal degenerative disease. The mechanism by which these mutations cause photoreceptor cell death, and the role aggregation plays in this process is still unclear. We recently demonstrated with the P23H and G188R rhodopsin mutants that the severity of aggregation observed in vitro is also reflected in vivo and impacts the rate of retinal degeneration. A Y178C rhodopsin mutant was investigated here to determine if this relationship applies broadly among mutations that cause misfolding and aggregation of the receptor. In vitro characterization indicated the Y178C rhodopsin mutant exhibits similar properties to the more severely aggregating G188R rhodopsin mutant, where the mutant is mislocalized to the endoplasmic reticulum in HEK293 cells and form aggregates that cannot be rescued by treatment with the retinoid 9-cis retinal. Despite these similarities in vitro, the Y178C rhodopsin mutant promoted a more severe retinal degeneration compared to the G188R mutant in vivo in mice. Aggregates of the Y178C rhodopsin mutant labeled by the dye PROTEOSTAT were morphologically similar to those formed by both the P23H and G188R rhodopsin mutants. There was, however, significantly greater photoreceptor cell death occurring independently of PROTEOSTAT-labeled aggregates in mice expressing the Y178C rhodopsin mutant compared to those expressing either the P23H or G188R rhodopsin mutants. Here, we demonstrate that PROTEOSTAT-labeled aggregates are not the sole cause of photoreceptor cell death promoted by the Y178C rhodopsin mutation in vivo, and there may be alternate aggregate forms contributing to cell death in these mice.

Lung carcinoma incidence and fatality rates remain among the highest on a global scale. The efficacy of targeted therapies and immunotherapies is commonly compromised by the emergence of drug resistance and other factors, resulting in a lack of durable therapeutic benefits. Ferroptosis, a distinct pattern of cell death marked by the buildup of iron-dependent lipid peroxides, has been shown to be a novel and potentially more effective treatment for lung carcinoma. However, the mechanism and regulatory network of ferroptosis are exceptionally complex, and many unanswered questions remain. In addition, research on ferroptosis in the diagnosis and treatment of lung cancer has been growing exponentially. Therefore, it is necessary to provide a thorough summary of the latest advancements in the field of ferroptosis. Here, we comprehensively analyze the mechanisms underlying the preconditions of ferroptosis, the defense system, and the associated molecular networks. The potential strategies of ferroptosis in the treatment of lung carcinoma are also highlighted. Targeting ferroptosis improves tumor cell drug resistance and enhances the effectiveness of targeted drugs and immunotherapies. These findings may shed fresh light on the diagnosis and management of lung carcinoma, as well as the development of drugs related to ferroptosis.

Colorectal cancer (CRC) is one of the most common tumors in the digestive system, and the majority of patients are found to be in advanced stages, which is a burden to human health all over the world. Moreover, in recent years, CRC has been progressively becoming younger, with an increasing incidence mainly among patients <50 years old. Despite the increase in awareness of CRC and the continuous improvement of medical treatment nowadays, the challenge of CRC still needs to be conquered. By now, the pathogenesis of CRC is complex and not fully understood. With the deepening of research, it has been revealed that PPARs, as a transcription factor, are inextricably linked to CRC. This article outlines the mechanisms by which PPARs are involved in CRC development. An in-depth understanding of the pathways related to PPARs may provide new ways of developing effective therapies for CRC with PPARs as potential targets.

Emerging evidence shows that lipid metabolic reprogramming plays a vital role in tumor metastasis. The effect and mechanism of fatty acids and lipid droplets (LDs), the core products of lipid metabolism, on the metastasis of oral squamous cell carcinoma (OSCC), need further exploration. In this study, the influence of palmitic acid (PA) and oleic acid (OA) on the migration and invasion ability of OSCC cells was determined by in vitro experiments. Genetic manipulation of PLIN2 was performed to explore its effect on the accumulation of LDs and OSCC metastasis. Possible mechanisms of these biological effects were clarified by detecting the levels of epithelial-mesenchymal transition (EMT) markers and phosphatidylinositol 3-kinase (PI3K) pathway proteins as well as conducting various bioinformatics analyses. The results indicated that PA/OA promoted the migration and invasion of OSCC cells and induced PLIN2-dependent LDs accumulation in vitro. Knockdown of PLIN2 inhibited the LDs accumulation and the migration and invasion of OSCC cells in vitro, while overexpression of PLIN2 enhanced those of OSCC cells in vitro and also promoted the metastasis of OSCC in vivo. Besides, PLIN2 up-regulation activated the PI3K pathway and subsequently enhanced EMT in OSCC cells in vitro. OSCC patients with higher PLIN2 expression possessed poorer prognosis and higher sensitivity to chemotherapy drugs (1S,3 R)-RSL3 and ML-210. In conclusion, PLIN2-dependent LDs accumulation could promote the metastasis of OSCC cells by regulating EMT. PLIN2 might be a potential therapeutic target for OSCC patients, especially those with obesity.

PARPis resistance is a challenge in the treatment of ovarian cancer. To investigate the potential mechanism involved in olaparib resistance of ovarian cancer, high-throughput sequencing was performed on olaparib-resistant SKOV3 cell line named SK/Ola. SPHK1 was upregulated in SK/Ola cells and was related to the PFS and OS in ovarian cancer patients. However, the effect and mechanism of SPHK1 on olaparib sensitivity in ovarian cancer were obscure. In this study, we found that SPHK1 promoted olaparib resistance. While, SPHK1 knockdown and SPHK1 inhibitor (PF-543 hydrochloride, named PF-543 in this article) enhanced the effect of olaparib on ovarian cancer cells. In mechanism, SPHK1 activated the NF-κB pathway through promoting p-IκBα degradation. Moreover, SPHK1 inhibited, but PF-543 activated ferroptosis in OC cells. Further investigation revealed that SPHK1 activated NF-κB p65, which in turn transcriptionally regulated NRF2 to inhibit ferroptosis in OC cells. Functionally, NF-κB p65 attenuated the PF-543-induced ferroptosis, and this effect was rescued by ferroptosis inducer erastin and RSL3. We conclude that SPHK1 inhibition triggers ferroptosis by restricting NF-κB-activated NRF2 transcription, thereby enhancing olaparib sensitivity in ovarian cancer. In vivo experiments also confirmed that the SPHK1 inhibitor increased olaparib sensitivity. A combination of SPHK1 inhibitors and olaparib may provide a therapeutic strategy for ovarian cancer.

DNA replication stress (RS), a prevalent feature of various malignancies, arises from both genetic mutations and genotoxic exposure. Elevated RS levels increase the vulnerability of cancer cells to ataxia telangiectasia and Rad3-related kinase inhibitors (ATRis). Here, we screened for DNA damage response inhibitors that enhance ATRi-induced cytotoxicity using SWI/SNF complex-deficient cells and identified a potent synergy between ATRi and poly(ADP-ribose) polymerase inhibitor (PARPi), particularly in SMARCA4-deficient cells. PARP inhibition triggers chromatin changes, namely elevated histone H3 at lysine 9 di-methylation (H3K9me2), a hallmark of facultative heterochromatin, increasing dependence on ATR activity for replication fork progression and cell survival. Interestingly, SMARCA4 deficient cells, intrinsically vulnerable to replication stress, exhibited exacerbated DNA damage upon combined ATRi and PARPi treatment in a Mre11- and Mus81-mediated manner. In vivo, combined treatment with intermittent ATRi and continuous PARPi showed greater inhibition of tumor growth than ATRi alone in SMARCA4-deficient lung adenocarcinoma xenograft models. These findings demonstrate that PARPi-induced heterochromatin amplifies RS and ATRi susceptibility, providing a potential rationale for therapeutic strategies targeting SMARCA4-deficient tumors.

Methyltransferase-like 1 (METTL1)-mediated m7G modification is a common occurrence in various RNA species, including mRNAs, tRNAs, rRNAs, and miRNAs. Recent evidence suggests that this modification is linked to the development of several cancers, making it a promising target for cancer therapy. However, the specific role of m7G modification in cutaneous squamous cell carcinoma (cSCC) is not well understood. In this study, we observed conspicuously elevated levels of METTL1 in cSCC tumors and cell lines. Inhibiting METTL1 led to reduced survival, migration, invasion, and xenograft tumor growth in cSCC cells. Mechanistically, through a combination of RNA sequencing, m7G methylated immunoprecipitation (MeRIP)-qPCR, and mRNA stability assays, we discovered that METTL1 is responsible for the m7G modification of ATF4 mRNA, leading to increased expression of ATF4. Importantly, we demonstrated that this modification is dependent on the methyltransferase activity of METTL1. Additionally, we observed a positive association between ATF4 expression and METTL1 levels in cSCC tumors. Intriguingly, restoring ATF4 expression in cSCC cells not only promoted glycolysis but also reversed the anti-tumor effects of METTL1 knockdown. In conclusion, our results underscore the critical role of METTL1 and m7G modification in cSCC tumorigenesis, suggesting a promising target for future cSCC therapies.

TP53 mutations are recognized to correlate with a worse prognosis in individuals with non-small cell lung cancer (NSCLC). There exists an immediate necessity to pinpoint selective treatment for patients carrying TP53 mutations. Potential drugs were identified by comparing drug sensitivity differences, represented by the half-maximal inhibitory concentration (IC50), between TP53 mutant and wild-type NSCLC cell lines using database analysis. In addition, clinical data from NSCLC patients were collected to evaluate both their TP53 status and their response to gemcitabine, thereby facilitating further validation. Subsequently, NSCLC cell lines with different TP53 status (A549 and H1299) were subjected to gemcitabine treatment to investigate the association between TP53 mutations and gemcitabine response. According to the dataset, NSCLC cell lines carrying TP53 mutations displayed heightened sensitivity to gemcitabine. From a clinical standpoint, patients exhibiting TP53 hotspot mutations demonstrated prolonged overall survival upon gemcitabine treatment. In vitro, overexpressing various hotspot TP53 mutations significantly sensitized H1299 cells to gemcitabine. Moreover, the knockdown of TP53 in A549 cells notably augmented sensitivity to gemcitabine treatment, as evidenced by cell viability and reproductive cell death assays. Conversely, the overexpression of wild-type TP53 in H1299 cells led to an increased resistance against gemcitabine. Gemcitabine is a treatment option for patients with non-small cell lung cancer (NSCLC) who carry TP53 hotspot mutations. This potential effectiveness might arise from its ability to disrupt DNA damage repair processes, leading to G2/M phase cell cycle arrest or an augmentation of mitotic abnormalities, eventually cause cell death. As a result, when planning treatment strategies for NSCLC patients possessing TP53 hotspot mutations, gemcitabine should be considered to incorporate into the indication.

Intestinal fibrosis, as a late-stage complication of inflammatory bowel disease (IBD), leads to bowel obstruction and requires surgical intervention, significantly lowering the quality of life of affected patients. SAA3, a highly conserved member of the serum amyloid A (SAA) apolipoprotein family in mice, is synthesized primarily as an acute phase reactant in response to infection, inflammation and trauma. An increasing number of evidence suggests that SAA3 exerts a vital role in the fibrotic process, even though the underlying mechanisms are not yet fully comprehended. This study utilized dextran sulfate sodium (DSS) to establish an IBD mouse model and observed that the SAA3-deficient mice exhibited more severe intestinal fibrosis. Our results further indicated that SAA3 genetic disruption in fibroblasts enhanced cell activation to myofibroblasts through HSPB1/NF-κB/TGF-β1/Smads signaling cascade, exacerbating the pathological phenotype of intestinal fibrosis. Collectively, our results shed novel lights on regulating SAA3 in intestinal fibrosis and indicate the potential to develop therapeutic strategies for IBD patients.