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Background Ferroptosis is a newly defined form of regulated cell death characterized by the iron-dependent accumulation of lipid peroxidation and is involved in various pathophysiological conditions, including cancer. Targeting ferroptosis is considered to be a novel anti-cancer strategy. The identification of FDA-approved drugs as ferroptosis inducers is proposed to be a new promising approach for cancer treatment. Despite a growing body of evidence indicating the potential efficacy of the anti-diabetic metformin as an anti-cancer agent, the exact mechanism underlying this efficacy has not yet been fully elucidated. Methods The UFMylation of SLC7A11 is detected by immunoprecipitation and the expression of UFM1 and SLC7A11 in tumor tissues was detected by immunohistochemical staining. The level of ferroptosis is determined by the level of free iron, total/lipid Ros and GSH in the cells and the morphological changes of mitochondria are observed by transmission electron microscope. The mechanism in vivo was verified by in situ implantation tumor model in nude mice. Results Metformin induces ferroptosis in an AMPK-independent manner to suppress tumor growth. Mechanistically, we demonstrate that metformin increases the intracellular Fe 2+ and lipid ROS levels. Specifically, metformin reduces the protein stability of SLC7A11, which is a critical ferroptosis regulator, by inhibiting its UFMylation process. Furthermore, metformin combined with sulfasalazine, the system x c − inhibitor, can work in a synergistic manner to induce ferroptosis and inhibit the proliferation of breast cancer cells. Conclusions This study is the first to demonstrate that the ability of metformin to induce ferroptosis may be a novel mechanism underlying its anti-cancer effect. In addition, we identified SLC7A11 as a new UFMylation substrate and found that targeting the UFM1/SLC7A11 pathway could be a promising cancer treatment strategy.

Autophagy is a conserved intracellular degradation system that plays a dual role in cell death; thus, therapies targeting autophagy in cancer are somewhat controversial. Ferroptosis is a new form of regulated cell death featured with the iron-dependent accumulation of lethal lipid ROS. This pathway is morphologically, biochemically and genetically distinct from other forms of cell death. Accumulating studies have revealed crosstalk between autophagy and ferroptosis at the molecular level. In this review, we summarize the mechanisms of ferroptosis and autophagy, and more importantly, their roles in the drug resistance of cancer. Numerous connections between ferroptosis and autophagy have been revealed, and a strong causal relationship exists wherein one process controls the other and can be utilized as potential therapeutic targets for cancer. The elucidation of when and how to modulate their crosstalk using therapeutic strategies depends on an understanding of the fine-tuned switch between ferroptosis and autophagy, and approaches designed to manipulate the intensity of autophagy might be the key.

Background Tamoxifen resistance remains a clinical challenge for hormone receptor-positive breast cancer. Recently, dysregulations in autophagy have been suggested as a potential mechanism for tamoxifen resistance. Although the long noncoding RNA H19 is involved in various stages of tumorigenesis, its role in tamoxifen resistance remains unknown. Here, we assessed the role of H19 in the development of tamoxifen-resistant breast cancer. Methods Quantitative real-time PCR analyzed expression of H19 in tamoxifen-resistant breast cancer tissues. Knockdown of H19 was used to assess the sensitivity to tamoxifen in vitro and in vivo. Both knockdown and overexpression of H19 were used to analyze the status of autophagy. Real-time quantitative methylation-specific polymerase chain reaction, chromatin immunoprecipitation, immunofluorescence, and Western blot were used to explore the tamoxifen resistance mechanism of H19. Results In this study, we observed that the expression of H19 was substantially upregulated in tamoxifen-resistant breast cancer cell line and tumor tissues, and knockdown of H19 enhanced the sensitivity to tamoxifen both in vitro and in vivo. Furthermore, knockdown of H19 significantly inhibited autophagy in MCF7 tamoxifen-resistant (MCF7/TAMR) cells. Conversely, overexpression of H19 promoted autophagy. Interestingly, overexpression of H19 in MCF7 tamoxifen-sensitive cells could recapitulate tamoxifen resistance. Moreover, an increase in methylation in the promoter region of Beclin1 was observed in MCF7/TAMR-shH19 cells. In the double knockdown groups, both shH19+shSAHH and shH19+shDNMT3B rescued the Beclin1 promoter region methylation levels and reactivated autophagy functions. A chromatin immunoprecipitation assay further validated that DNMT3B binds to the Beclin1 promoter region and the knockdown of H19 increases this binding. Conclusions Our findings demonstrate that H19 induces autophagy activation via the H19/SAHH/DNMT3B axis, which could contribute to tamoxifen resistance in breast cancer.

Circulating tumor cells (CTCs) are cells that shed from a primary tumor and travel through the bloodstream. Studying the functional and molecular characteristics of CTCs may provide in-depth knowledge regarding highly lethal tumor diseases. Researchers are working to design devices and develop analytical methods that can capture and detect CTCs in whole blood from cancer patients with improved sensitivity and specificity. Techniques using whole blood samples utilize physical prosperity, immunoaffinity or a combination of the above methods and positive and negative enrichment during separation. Further analysis of CTCs is helpful in cancer monitoring, efficacy evaluation and designing of targeted cancer treatment methods. Although many advances have been achieved in the detection and molecular characterization of CTCs, several challenges still exist that limit the current use of this burgeoning diagnostic approach. In this review, a brief summary of the biological characterization of CTCs is presented. We focus on the current existing CTC detection methods and the potential clinical implications and challenges of CTCs. We also put forward our own views regarding the future development direction of CTCs.

The tumor microenvironment is proposed to contribute substantially to the progression of cancers, including breast cancer. Cancer‐associated fibroblasts (CAFs) are the most abundant components of the tumor microenvironment. Studies have revealed that CAFs in breast cancer originate from several types of cells and promote breast cancer malignancy by secreting factors, generating exosomes, releasing nutrients, reshaping the extracellular matrix, and suppressing the function of immune cells. CAFs are also becoming therapeutic targets for breast cancer due to their specific distribution in tumors and their unique biomarkers. Agents interrupting the effect of CAFs on surrounding cells have been developed and applied in clinical trials. Here, we reviewed studies examining the heterogeneity of CAFs in breast cancer and expression patterns of CAF markers in different subtypes of breast cancer. We hope that summarizing CAF‐related studies from a historical perspective will help to accelerate the development of CAF‐targeted therapeutic strategies for breast cancer.

Immune checkpoint inhibition targeting the PD-1/PD-L1 pathway has become a powerful clinical strategy for treating cancer, but its efficacy is complicated by various resistance mechanisms. One of the reasons for the resistance is the internalization and recycling of PD-L1 itself upon antibody binding. The inhibition of lysosome-mediated degradation of PD-L1 is critical for preserving the amount of PD-L1 recycling back to the cell membrane. In this study, we find that Hsc70 promotes PD-L1 degradation through the endosome-lysosome pathway and reduces PD-L1 recycling to the cell membrane. This effect is dependent on Hsc70-PD-L1 binding which inhibits the CMTM6-PD-L1 interaction. We further identify an Hsp90α/β inhibitor, AUY-922, which induces Hsc70 expression and PD-L1 lysosomal degradation. Either Hsc70 overexpression or AUY-922 treatment can reduce PD-L1 expression, inhibit tumor growth and promote anti-tumor immunity in female mice; AUY-922 can further enhance the anti-tumor efficacy of anti-PD-L1 and anti-CTLA4 treatment. Our study elucidates a molecular mechanism of Hsc70-mediated PD-L1 lysosomal degradation and provides a target and therapeutic strategies for tumor immunotherapy. Hsc70 (heat shock protein family A member 8) is a cytoplasmic chaperone protein involved in endosomal micro-autophagy and chaperone-mediated autophagy. Here the authors report that Hsc70 promotes lysosomal degradation of PD-L1 and that its overexpression promotes anti-tumor immune responses in preclinical cancer models.

Despite advances in cancer treatment, immune checkpoint blockade (ICB) only achieves complete response in some patients, illustrating the need to identify resistance mechanisms. Using an ICB-insensitive tumor model, here we discover cisplatin enhances the anti-tumor effect of PD-L1 blockade and upregulates the expression of Ariadne RBR E3 ubiquitin-protein ligase 1 (ARIH1) in tumors. Arih1 overexpression promotes cytotoxic T cell infiltration, inhibits tumor growth, and potentiates PD-L1 blockade. ARIH1 mediates ubiquitination and degradation of DNA-PKcs to trigger activation of the STING pathway, which is blocked by the phospho-mimetic mutant T68E/S213D of cGAS protein. Using a high-throughput drug screen, we further identify that ACY738, less cytotoxic than cisplatin, effectively upregulates ARIH1 and activates STING signaling, sensitizing tumors to PD-L1 blockade. Our findings delineate a mechanism that tumors mediate ICB resistance through the loss of ARIH1 and ARIH1-DNA-PKcs-STING signaling and indicate that activating ARIH1 is an effective strategy to improve the efficacy of cancer immunotherapy. Loss of the E3 ubiquitin-protein ligase ARIH1 has been associated with cancer escape from anti-tumor immunity. Here the authors show that ARIH1 mediated ubiquitination and degradation of DNA-PKcs trigger activation of STING pathway in tumor cells, sensitizing tumors to immune checkpoint blockade.

Ferroptosis, which is characterized by the accumulation of intracellular iron and subsequent lipid peroxidation, is a newly discovered form of regulated cell death and plays an important role in tumor suppression. Herein, we showed that Polyphyllin III, which is a major saponin extracted from Paris polyphylla rhizomes, exerted its proliferation-inhibitory effect on MDA-MB-231 triple-negative breast cancer cells mainly through ACSL4-mediated lipid peroxidation elevation and ferroptosis induction. ACSL4 deletion partly attenuated Polyphyllin III-induced ferroptosis. Polyphyllin III treatment also induced KLF4-mediated protective upregulation of xCT, which is the negative regulator of ferroptosis. Interestingly, combination with the xCT inhibitor sulfasalazine (SAS) or downregulation of KLF4 sensitized MDA-MB-231 cells to Polyphyllin III. Furthermore, in vivo xenograft models, SAS significantly sensitized MDA-MB-231 breast cancer cells to Polyphyllin III, likely by enhancing intracellular lipid peroxidation and ferroptosis. The results of this study collectively demonstrated that Polyphyllin III exerts its anticancer effect by inducing ferroptosis via ACSL4 in MDA-MB-231 breast cancer cells. More importantly, we observed for the first time that KLF4-mediated xCT upregulation serves as negative feedback during ferroptosis progression, which might contribute to drug resistance in cancer treatment.

Background Early-stage Luminal A breast cancer generally has a favorable prognosis, yet some patients experience recurrence, presenting a challenge in understanding the underlying genetic factors. This study aimed to identify genetic mutations associated with recurrence in early-stage Luminal A breast cancer patients through whole-exome sequencing (WES). Methods We collected formalin-fixed paraffin-embedded samples from 34 patients and divided them into two groups: 17 patients with recurrence within five years post-surgery (recurrence group) and 17 patients with no recurrence for over five years (control group). The extracted DNA went through library preparation and was subjected to WES. Sequencing data went through quality control, alignment, and mutation identification. Functional enrichment analyses were conducted to explore the biological implications of the mutations. Results We generated on average ~ 11 Gb raw sequencing data for each sample and identified 7,066 nonsynonymous mutations. The recurrence group exhibited a higher mutation rate (11.48 mutations/Mb) compared with the control group (9.18 mutations/Mb, p  < 0.05). A significant negative correlation was observed between disease-free survival time and the number of mutations ( p  < 0.05). Eight genes (MICALCL, G6PD, OR8U1, PCLO, OR8U8, ZCCHC18, CPED1, HMCN1) were significantly associated with early recurrence ( p  < 0.05). Functional enrichment analyses revealed that these genes were involved in pathways like mismatch repair and immune response. Conclusions This study identified specific genetic mutations linked to early recurrence in Luminal A breast cancer, highlighting potential biomarkers for predicting patient outcomes and personalizing cancer treatment. Our study also showed that state-of-the-art WES can extract biologically and clinically meaningful mutation signatures from routinely stored FFPE tissues, unlocking archived specimens for large-scale biomarker discovery.

Ferroptosis is a recently discovered distinct type of regulated cell death caused by the accumulation of lipid-based ROS. Metabolism and expression of specific genes affect the occurrence of ferroptosis, making it a promising therapeutic target to manage cancer. Here, we describe the current status of ferroptosis studies in breast cancer and trace the key regulators of ferroptosis back to previous studies. We also compare ferroptosis to common regulated cell death patterns and discuss the sensitivity to ferroptosis in different subtypes of breast cancer. We propose that viewing ferroptosis-related studies from a historical angle will accelerate the development of ferroptosis-based biomarkers and therapeutic strategies in breast cancer.