Cell Death & Disease最新文献

Arachidonate 15-lipoxygenase type B (ALOX15B) peroxidises polyunsaturated fatty acids to their corresponding fatty acid hydroperoxides, which are subsequently reduced into hydroxy-fatty acids. A dysregulated abundance of these biological lipid mediators has been reported in the skin and blood of psoriatic compared to healthy individuals. RNAscope and immunohistochemistry revealed increased ALOX15B expression in lesional psoriasis samples. Using a cytokine cocktail containing IL-17A, interferon-gamma and tumour necrosis factor-alpha to produce a psoriasis-like phenotype, a role for ALOX15B in human epidermal keratinocyte inflammation was investigated. siRNA-mediated silencing of ALOX15B increased CCL2 expression and secretion. In addition to CCL2, secretion of CCL5 and CXCL10 were elevated in skin equivalents treated with lipoxygenase inhibitor ML351. Inhibition of the JAK1/STAT1 pathway reversed the enhanced CCL2 expression found with ALOX15B silencing. Previous studies have linked epidermal growth factor receptor (EGFR) inhibition with the upregulation of cytokines including CCL2, CCL5 and CXCL10. ALOX15B silencing reduced EGFR expression and inhibition of EGFR signalling potentiated the effect of ALOX15B silencing on increased CCL2, CCL5 and CXCL10 expression. Confirming previous findings, gene expression of cholesterol biosynthesis genes was reduced via reduced ERK phosphorylation. Reduced ERK phosphorylation was dependant on EGFR and NRF2 activation. Furthermore, plasma membrane lipids were investigated via confocal microscopy, revealing reduced cholesterol and lipid rafts. This study suggests a role for ALOX15B in keratinocyte inflammation through modulation of lipid peroxidation and the EGFR/JAK1/STAT1 signalling axis.

The spatial role of M1 and M2 tumor-associated macrophages (M1/M2 TAMs) in precision medicine remains unclear. EGFR and TP53 are among the most frequently mutated genes in lung adenocarcinoma. We characterized the mutation status and density of M1/M2 TAMs within tumor islets and stroma in 117 lung adenocarcinomas using next-generation sequencing and immunohistochemistry, respectively. Stromal M1 TAMs were positively correlated with disease progression and smoking history. In contrast, islet M1/M2 TAMs were predominantly found in tumors with wild-type TP53 (wtp53) but not associated with EGFR status. The presence of wtp53 was associated with the spatial distribution of M1/M2 TAMs in tumor islets and stroma. Additionally, dominance of islet M1 TAMs and M1-signature were significantly associated with improved survival in patients with wtp53 lung adenocarcinoma, unlike in those with mutant TP53. Conditioned medium from M1 macrophages (M1 CM) induced apoptosis in wtp53 cells through increased p53 accumulation. We found that interferons in M1 CM activate JAK1/TYK2 via IFNARs, leading to enhanced STAT1 expression and Y701 phosphorylation. This activation facilitates p53-STAT1 interactions, reduces the interaction between p53 and MDM2, and subsequently decreases p53 ubiquitination. M1 CM inhibited tumorigenesis, and silencing p53 reduced the anti-tumor efficacy of polyinosinic:polycytidylic acid (poly I:C) in vivo. Furthermore, higher M1-signature was significantly associated with better responses and survival following anti-PD1 treatment in wtp53 melanomas. IFNs/STAT1/p53 signaling was critical for the anti-tumor activity of M1 macrophages. These findings suggest that p53 modulates the spatial balance of M1/M2 TAMs, and the tumoricidal effects of M1 TAMs depend on p53 status. Thus, p53 companion diagnostics could facilitate the development of M1-oriented therapies, which may be particularly beneficial for wtp53 patients when combined with immunotherapy.

Sarcoglycanopathies are heterogeneous proximo-distal diseases presenting severe muscle alterations. Although there are 6 different sarcoglycan isoforms, sarcoglycanopathies are caused exclusively by mutations in genes coding for one of the four sarcoglycan transmembrane proteins (alpha, beta, gamma and delta) forming the sarcoglycan complex (SGC) in skeletal and cardiac muscle. Little is known about the different roles of the SGC beyond the dystrophin glycoprotein complex (DGC) structural role. Here, we show that SGC proteins are enriched at the post-synaptic membrane of neuromuscular junctions (NMJs). Using a mouse model lacking the beta-sarcoglycan subunit, we describe for the first time that the loss of the SGC in the NMJ area results in alterations of pre- and postsynaptic membrane, as well as a significant reduction of membrane potential. Moreover, using different denervated wild-type mouse models, we demonstrate that nerve presence precedes the sarcoglycan enrichment at NMJ, suggesting a nerve-dependent sarcoglycan expression. Altogether, our findings suggest that pathological decline should no longer be understood only in terms of sarcolemma damage but also in terms of sarcoglycans' participation in the NMJ. Henceforth, our work paves the way for the identification of new mechanisms involving sarcoglycans and new approaches for the treatment of sarcoglycanopathies.

Malignant melanoma represents the fifth most common cancer in the world and its incidence is rising. Novel therapies targeting receptor tyrosine kinases, kinases and immune checkpoints have been employed with a significant improvement of the overall survival and long-term disease containment. Nevertheless, the disease often progresses and becomes resistant to the therapies. As such, the discovery of new targets and drugs for advanced melanoma still remains a difficult task. Gender disparities, with a female advantage in melanoma incidence and outcome, have been reported. Although emerging studies support the pro-tumorigenic role of androgen/androgen receptor axis in melanoma, the molecular bases of such evidence are still under intense investigation. We now report that ligand activation of the androgen receptor drives melanoma invasiveness and its escape from natural killer-mediated cytotoxic effect. By combining different experimental approaches, we observe that melanoma escape is mediated by the androgen-triggered shedding of the surface molecule MICA. Specific blockade of ADAM10 or androgen receptor impairs the androgen-induced MICA shedding and melanoma immune-escape. Further, the increase in MICA serum levels correlates with a poor outcome in melanoma patients treated with the anti-PD-1 monoclonal antibody, pembrolizumab. At last, melanoma cells depleted of the androgen receptor become more responsive to the most commonly used immunocheckpoint inhibitors, suggesting that the receptor dampens the immunotherapy efficacy. Taken together, our findings identify the androgen receptor as a diagnostic guidance in melanoma and support the repositioning of AR blockers in clinical management of patients.

Compromised vascular integrity facilitates the cancer cells extravasation and metastasis. However, the mechanisms leading to a disruption in vascular integrity in colorectal cancer (CRC) remain unclear. In this study, PCDH17 expression was higher in the vascular endothelial cells of colon cancer with distant metastasis, and the rates of PCDH17⁺ endothelial cells (ECs) was associated with the M stage in clinical pathological characteristics analysis and correlated with a poor survival prognosis. The liver and lung metastatic dissemination of MC-38 was significantly decreased in PCDH17^-/-mice. The ubiquitination and degradation of VEGFR2 was prevented by the interaction between PCDH17 and the E3 ubiquitin ligase MARCH5, which causing the separation of internalized VE-cadherin, and increased the vascular permeability and metastasis of CRC. These results highlight the importance of PCDH17 in maintaining vascular integrity, which has emphasis for endothelial barrier function in metastatic cancer. PCDH17 has the potential to be a marker for predicting tumor metastasis as well as a viable treatment target for CRC.

This study suggests a modified model of TNFR1-induced complex I-mediated NFκB signaling. Evaluation of a panel of five tumor cell lines (HCT116-PIK3CAmut, SK-MEL-23, HeLa-RIPK3, HT29, D10) with TRAF2 knockout revealed in two cell lines (HT29, HeLa-RIPK3) a sensitizing effect for death receptor-induced necroptosis and in one cell line (D10) a mild sensitization for TNFR1-induced apoptosis. TRAF2 deficiency inhibited death receptor-induced classical NFκB-mediated production of IL-8 only in a subset of cell lines and only partly. TRAF5, furthermore, failed to improve DR-induced NFκB signaling in HCT116-PIK3CAmut and HCT116-PIK3CAmut-TRAF2_KO cells. These findings argue for a non-obligatory role of TRAF2 in death receptor-induced classical NFκB signaling. Similar as in TRAF2-deficient cells, TNF- and CD95L-induced NFκB signaling was found to be only poorly affected in RIPK1_KO cells and in cells treated with the RIPK1-specific PROTAC LD4172. Intriguingly, however, death receptor-induced NFκB signaling was completely inhibited in HCT116-PIK3CAmut cells double deficient for TRAF2 and RIPK1 and in TRAF2-deficient cells treated with LD4172. Moreover, with exception of recruitment of TRADD, acting upstream to TRAF2 and parallel to RIPK1, TNFR1 signaling complex formation was abrogated in TRAF2-RIPK1 DKO cells. Based on our findings, two distinguishable types of TNFR1-interacting complexes promote TNF-induced NFκB signaling: First, a TRADD-TRAF2/cIAP utilizing complex Ia which becomes evident in RIPK1-deficient cells. Second, a non-modified RIPK1 utilizing complex Ib which acts in TRADD- or TRAF2-deficient cells. Complex Ia and Ib may furthermore interact and cooperate to ubiquitinate RIPK1 resulting in a modified complex Ia/b preventing complex Ia and Ib to convert to the established TNFR1-induced cytotoxic complexes IIa and IIb.

Psoriasis is a chronic inflammatory skin disorder characterized by hyperproliferation of keratinocytes and persistent inflammation. Although persistent activation of signal transducer and activator of transcription 3 (STAT3) is implicated in its pathogenesis, the mechanisms underlying the sustained STAT3 activation remain poorly understood. Here, we identify sphingosine-1-phosphate receptor 3 (S1PR3) as a critical regulator of STAT3 activation and psoriasis pathogenesis, orchestrating a self-amplifying circuit that sustains keratinocyte hyperproliferation and chronic inflammation. S1PR3 expression is markedly elevated in psoriatic lesions and correlates with disease severity. Using genetic and pharmacological approaches, we reveal a novel S1PR3-Src-STAT3 signaling axis that drives both early and prolonged STAT3 activation in keratinocytes. Mechanistically, S1PR3 operates through Gαi/PKA-mediated Src activation, enhancing STAT3 phosphorylation and subsequent transcriptional activity. Importantly, we reveal a previously unrecognized positive feedback loop wherein activated STAT3 directly upregulates S1PR3 expression, perpetuating inflammation and hyperproliferation. Genetic deletion of S1pr3 in mice or pharmacological inhibition of S1PR3 significantly attenuates psoriasis-like skin inflammation, decreasing epidermal hyperplasia, dermal angiogenesis, and inflammatory mediator production. These findings provide new insights into the molecular mechanisms underlying psoriasis and identify S1PR3 as a promising therapeutic target. Our study suggests that disrupting the S1PR3-STAT3 feedback loop may offer a novel strategy for treating psoriasis and potentially other chronic inflammatory diseases driven by persistent STAT3 activation.

Estrogen receptor positive (ER+) breast cancer accounts for approximately 70% of cases. Endocrine therapies targeting estrogen are the first line therapies for ER+ breast cancer. However, resistance to these therapies occurs in about half of patients, leading to decreased survival rates. Inducing ferroptosis is a promising therapeutic strategy for cancer treatment for refractory and malignant cancers including triple-negative breast cancer. Nevertheless, ER+ breast cancer is relatively resistant to ferroptosis inducers. Here, we uncovered that ERα suppressed ferroptosis in ER+ breast cancer. Silencing ERα triggered ferroptosis, which was attenuated by ferroptosis inhibitor Ferrostatin-1, and was enhanced by ferroptosis inducer Erastin. Mechanistically, ERα transcriptionally upregulated the expression of SLC7A11 and SLC3A2, two subunits of the system x_c^-, which is one key inhibitory regulator of ferroptosis. Overexpression of the exogenous SLC7A11 and SLC3A2 was able to mitigate ferroptosis induced by ERα inhibition. Moreover, SLC7A11 and SLC3A2 levels were elevated in endocrine-resistant breast cancer cells and tumors. Importantly, the system x_c^- inhibitor Sorafenib or Imidazole ketone erastin effectively inhibited the growth of tamoxifen-resistant breast cells in vitro and in vivo. In conclusion, our data reveal that targeting estrogen-regulated SLC7A11 and SLC3A2 enhances ferroptosis in ER+ breast cancer, offering a novel therapeutic option for patients with ER+ breast cancer, particularly those with endocrine resistance.