Ferroptosis, a form of regulated necrosis driven by iron-dependent peroxidation of phospholipids, is regulated by cellular metabolism, redox homeostasis, and various signaling pathways related to ...cancer. In this study, we found that activating mutation of phosphatidylinositol 3-kinase (PI3K) or loss of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) function, highly frequent events in human cancer, confers ferroptosis resistance in cancer cells, and that inhibition of the PI3K-AKT-mTOR signaling axis sensitizes cancer cells to ferroptosis induction. Mechanistically, this resistance requires sustained activation of mTORC1 and the mechanistic target of rapamycin (mTOR)C1-dependent induction of sterol regulatory element-binding protein 1 (SREBP1), a central transcription factor regulating lipid metabolism. Furthermore, stearoyl-CoA desaturase-1 (SCD1), a transcriptional target of SREBP1, mediates the ferroptosis-suppressing activity of SREBP1 by producing monounsaturated fatty acids. Genetic or pharmacologic ablation of SREBP1 or SCD1 sensitized ferroptosis in cancer cells with PI3K-AKT-mTOR pathway mutation. Conversely, ectopic expression of SREPB1 or SCD1 restored ferroptosis resistance in these cells, even when mTORC1 was inhibited. In xenograft mouse models for PI3K-mutated breast cancer and PTEN-defective prostate cancer, the combination of mTORC1 inhibition with ferroptosis induction resulted in near-complete tumor regression. In conclusion, hyperactive mutation of PI3K-AKT-mTOR signaling protects cancer cells from oxidative stress and ferroptotic death through SREBP1/SCD1-mediated lipogenesis, and combination of mTORC1 inhibition with ferroptosis induction shows therapeutic promise in preclinical models.
Role of Mitochondria in Ferroptosis Gao, Minghui; Yi, Junmei; Zhu, Jiajun ...
Molecular cell,
01/2019, Letnik:
73, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Ferroptosis is a regulated necrosis process driven by iron-dependent lipid peroxidation. Although ferroptosis and cellular metabolism interplay with one another, whether mitochondria are involved in ...ferroptosis is under debate. Here, we demonstrate that mitochondria play a crucial role in cysteine-deprivation-induced ferroptosis but not in that induced by inhibiting glutathione peroxidase-4 (GPX4), the most downstream component of the ferroptosis pathway. Mechanistically, cysteine deprivation leads to mitochondrial membrane potential hyperpolarization and lipid peroxide accumulation. Inhibition of mitochondrial TCA cycle or electron transfer chain (ETC) mitigated mitochondrial membrane potential hyperpolarization, lipid peroxide accumulation, and ferroptosis. Blockage of glutaminolysis had the same inhibitory effect, which was counteracted by supplying downstream TCA cycle intermediates. Importantly, loss of function of fumarate hydratase, a tumor suppressor and TCA cycle component, confers resistance to cysteine-deprivation-induced ferroptosis. Collectively, this work demonstrates the crucial role of mitochondria in cysteine-deprivation-induced ferroptosis and implicates ferroptosis in tumor suppression.
Induction of ferroptosis has emerged as a potential cancer therapeutic approach. In this issue of Cell Chemical Biology, Zhang et al. (2019) demonstrate the anticancer efficacy and safety of the ...ferroptosis inducer imidazole ketone erastin (IKE) in a xenograft model by using a nanoparticle-based delivery system.
Laser direct metal deposition (DMD) is an efficient and flexible additive manufacturing technique which has broad application prospects, but it is also limited due to defects and mechanical ...anisotropy. Laser remelting (LR) is a process that after each layer is deposited, re-scan the deposition layer with the same slice data but without powder deliver, and it is often used during selective laser melting. Herein, LR process has been applied during the DMD process of a 17-4 PH steel to enhance the densification level and relieve the mechanical anisotropy. It is found that the thermal history, porosity and microstructural evolution are dependent on the LR energy density. Moreover, the roughness of top surface of the deposited layer and intralayer porosity decrease with increase of the laser remelting energy density. While for interlayer defects, there is an optimal LR energy density corresponding to the lowest interlayer porosity. Furthermore, LR process can enhance the holding time at high temperature, even sometimes heat the sample above Ac1, resulting in change in contents of austenite and carbide. In addition, LR process greatly dilutes the pre-solidified texture. It was also proved that the flat defects in-plane to the interlayer and the anisotropy of the crystallographic orientations are extremely harmful for the mechanical isotropy of the DMDed samples. Finally, sample manufactured with laser remelting at 15.0 J/mm2 has the lowest porosity and most random crystallographic orientations resulting in near isotropous tensile strength, but the contribution of laser remelting to eliminate anisotropy in elongation is limited because of the interlayer defects.
Objective
Patients with bone metastasis (BM) of small cell lung cancer (SCLC) have a poor prognosis. We aimed to identify predictors and prognostic factors in patients with BM of SCLC and construct ...nomograms to predict BM.
Methods
We retrospectively analyzed 18,187 cases from the Surveillance, Epidemiology, and End Results database reported between 2010 and 2016. Differences in overall survival (OS) and cancer-specific survival (CSS) were evaluated after propensity score matching. Independent predictors for BM and prognostic factors for patients with BM of SCLC were determined using univariate and multivariate regression analyses. Two nomograms were constructed and evaluated using C-statistics.
Results
BM was observed in 4014 (22.07%) patients. Kaplan–Meier survival analysis revealed significant differences between BM and non-BM groups. The median OS for patients with and without BM was 6 and 7 months, respectively. The median CSS for patients with and without BM was 9 and 13 months, respectively. Age, sex, tumor size, N stage, chemotherapy, surgery, radiotherapy, and liver/brain/lung metastases were related to BM and independent prognostic factors for OS and CSS. Diagnostic and prognostic nomograms were generated.
Conclusion
Our nomograms predicted the incidence of BM and the 5-month survival rate of patients with SCLC and BM.
In recent years, the emergence of novel 2D monoelemental materials (Xenes), e.g., graphdiyne, borophene, phosphorene, antimonene, bismuthene, and stanene, has exhibited unprecedented potentials for ...their versatile applications as well as addressing new discoveries in fundamental science. Owing to their unique physicochemical, optical, and electronic properties, emerging Xenes have been regarded as promising candidates in the community of single‐atom catalysts (SACs) as single‐atom active sites or support matrixes for significant improvement in intrinsic activity and selectivity. In order to comprehensively understand the relationships between the structure and property of Xene‐based SACs, this review represents a comprehensive summary from theoretical predictions to experimental investigations. Firstly, theoretical calculations regarding both the anchoring of Xene‐based single‐atom active sites on versatile support matrixes and doping/substituting heteroatoms at Xene‐based support matrixes are briefly summarized. Secondly, controlled synthesis and precise characterization are presented for Xene‐based SACs. Finally, current challenges and future opportunities for the development of Xene‐based SACs are highlighted.
The controlled synthesis, precise characterization, and catalytic applications of emerging Xene‐based single‐atom catalysts from theoretical predictions to experimental investigations are the focus of this review. It is envisioned that this timely review can shed light on new designs of high‐performance Xene‐related single‐atom nanoplatforms for next‐generation chemical and energy conversion.
Immune checkpoint inhibitors (ICIs) have achieved promising effects in patients with non-small cell lung cancer (NSCLC). However, not all patients with NSCLC benefit from immunotherapy. There is an ...urgent need to explore biomarkers that could predict the survival outcomes and therapeutic efficacy in advanced NSCLC patients treated with immunotherapy. In this study, we aimed to assess the changes in peripheral blood lymphocyte subsets and their association with the therapeutic efficacy and clinical prognosis of advanced NSCLC patients treated with immunotherapy.
A total of 276 patients with advanced NSCLC were enrolled. Peripheral blood lymphocyte subsets including CD4
T cells, CD8
T cells, CD4
/CD8
ratio, NK cells, Tregs and B cells were collected before any treatment, before immunotherapy or chemotherapy, and after 4 cycles of immunotherapy or chemotherapy. T-test was used to analyze the factors influencing lymphocyte subsets and their changes before and after therapy. Logistic regression was used to plot ROC curves and analyze the relationship between lymphocyte subsets and therapeutic efficacy. Log-rank test and Cox regression model were used to evaluate the relationship between lymphocyte subsets and progression-free survival (PFS).
Gender, distant metastasis, and EGFR mutation status are known to affect the proportion of peripheral blood lymphocyte subsets in patients with advanced NSCLC. The proportions of CD4
T cells, CD8
T cells, Tregs and B cells were found to decrease after chemotherapy as compared to the baseline. The proportion of CD4
T cells, CD8
T cells, CD4
/CD8
ratio, NK cells and Tregs were higher after immunotherapy than after chemotherapy. Compared to the baseline, the effective group showed significant increase in the proportions of CD4
T cells, CD4
/CD8
ratio, NK cells and Tregs, and the number of CD8
T cells was significantly lower in the peripheral blood after 4 cycles of immunotherapy. On the contrary, the ineffective group did not show any significant differences in the above parameters. Baseline CD4
T cells and NK cells were independent predictors of immunotherapy efficacy and PFS. Baseline Tregs were independent predictor of immunotherapy efficacy.
Immune checkpoint inhibitors induced changes in the proportion of peripheral blood lymphocyte subsets in patients that responded well to immunotherapy. The levels of the different lymphocyte subsets could serve as valuable predictive biomarkers of efficacy and clinical prognosis for NSCLC patients treated with immunotherapy.
With rapid and continuous consumption of nonrenewable energy, solar energy can be utilized to meet the energy requirement and mitigate environmental issues in the future. To attain a sustainable ...society with an energy mix predominately dependent on solar energy, photoelectrochemical (PEC) device, in which semiconductor nanostructure‐based photocatalysts play important roles, is considered to be one of the most promising candidates to realize the sufficient utilization of solar energy in a low‐cost, green, and environmentally friendly manner. Interface engineering of semiconductor nanostructures has been qualified in the efficient improvement of PEC performances including three basic steps, i.e., light absorption, charge transfer/separation, and surface catalytic reaction. In this review, recently developed interface engineering of semiconductor nanostructures for direct and high‐efficiency conversion of sunlight into available forms (e.g., chemical fuels and electric power) are summarized in terms of their atomic constitution and morphology, electronic structure and promising potential for PEC applications. Extensive efforts toward the development of high‐performance PEC applications (e.g., PEC water splitting, PEC photodetection, PEC catalysis, PEC degradation and PEC biosensors) are also presented and appraised. Last but not least, a brief summary and personal insights on the challenges and future directions in the community of next‐generation PEC devices are also provided.
This review focuses on the recently developed interface engineering of semiconductor nanostructures for direct and high‐efficiency conversion of sunlight into available forms, and extensive efforts toward the development of versatile high‐performance photoelectrochemical (PEC) applications. It is envisioned that this review can pave the way to the development of high‐efficiency advanced nanostructures for modern PEC devices.
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