The accumulation of lipid peroxides is recognized as a determinant of the occurrence of ferroptosis. However, the sensors and amplifying process of lipid peroxidation linked to ferroptosis remain ...obscure. Here we identify PKCβII as a critical contributor of ferroptosis through independent genome-wide CRISPR-Cas9 and kinase inhibitor library screening. Our results show that PKCβII senses the initial lipid peroxides and amplifies lipid peroxidation linked to ferroptosis through phosphorylation and activation of ACSL4. Lipidomics analysis shows that activated ACSL4 catalyses polyunsaturated fatty acid-containing lipid biosynthesis and promotes the accumulation of lipid peroxidation products, leading to ferroptosis. Attenuation of the PKCβII-ACSL4 pathway effectively blocks ferroptosis in vitro and impairs ferroptosis-associated cancer immunotherapy in vivo. Our results identify PKCβII as a sensor of lipid peroxidation, and the lipid peroxidation-PKCβII-ACSL4 positive-feedback axis may provide potential targets for ferroptosis-associated disease treatment.
Annexin A1 (ANXA1) is dysregulated in the various tumors. However, the role and mechanism of ANXA1 in the cancers are poorly understood. In this study, we first showed a clinically positive ...correlation between ANXA1 and autophagy-associated protein SQSTM1 expression in nasopharyngeal carcinoma (NPC) and ANXA1-regulating SQSTM1 expression through autophagy, and further demonstrated that ANXA1 inhibited BECN1 and ATG5-dependent autophagy in the NPC cells. Using phospho-kinase antibody array to identify signaling through which ANXA1 regulated NPC cell autophagy, we found that ANXA1-suppressed autophagy was associated with PI3K/AKT signaling activation. We also showed that ANXA1 expression was significantly increased in the NPCs with metastasis relative to NPCs without metastasis and positively correlated with lymphonode and distant metastasis; high ANXA1 expression in the NPC cells promoted in vitro tumor cell migration and invasion and in vivo metastasis. Lastly, we showed that inhibition of autophagy restored the ability of tumor cell migration and invasion, epithelial-mesenchymal transition (EMT)-like alterations and in vivo metastasis in the ANXA1 knockdown NPC cells with autophagy activation; ANXA1-suppresed autophagy induced EMT-like alterations possibly by inhibiting autophagy-mediated degradation of Snail. Our data suggest that ANXA1-suppressed autophagy promotes NPC cell migration, invasion and metastasis by activating PI3K/AKT signaling pathway, highlighting that the activation of autophagy may inhibit metastasis of NPC with high ANXA1 expression.
Despite more effective chemotherapy combined with limb-salvage surgery for the osteosarcoma treatment, survival rates for osteosarcoma patients have stagnated over the past three decades due to the ...poor prognosis. Osteosarcoma cancer stem cells (OSCs) are responsible for the growth and metastasis of osteosarcoma. The existence of OSCs offers a theoretical explanation for therapeutic failures including tumor recurrence, metastasis, and drug resistance. Understanding the pathways that regulate properties of OSCs may shed light on mechanisms that lead to osteosarcoma and suggest better modes of treatment. In this study, we showed that the expression level of Kruppel-like factor 4 (KLF4) is highly associated with human osteosarcoma cancer stemness. KLF4-overexpressed osteosarcoma cells displayed characteristics of OSCs: increased sphere-forming potential, enhanced levels of stemness-associated genes, great chemoresistance to adriamycin and CDDP, as well as more metastasis potential. Inversely, KLF4 knockdown could reduce colony formation in vitro and inhibit tumorigenesis in vivo, supporting an oncogenic role for KLF4 in osteosarcoma pathogenesis. Furthermore, KLF4 was shown to activate the p38 MAPK signaling pathway to promote cancer stemness. Altogether, our studies uncover an essential role for KLF4 in regulation of OSCs and identify KLF4-p38 MAPK axis as a potential therapeutic target for osteosarcoma treatment.
In recent years, studies have shown that the secretome of bone marrow mesenchymal stromal cells (BMSCs) contains many growth factors, cytokines, and antioxidants, which may provide novel approaches ...to treat ischemic diseases. Furthermore, the secretome may be modulated by hypoxic preconditioning. We hypothesized that conditioned medium (CM) derived from BMSCs plays a crucial role in reducing tissue damage and improving neurological recovery after ischemic stroke and that hypoxic preconditioning of BMSCs robustly improves these activities. Rats were subjected to ischemic stroke by middle cerebral artery occlusion and then intravenously administered hypoxic CM, normoxic CM, or Dulbecco modified Eagle medium (DMEM, control). Cytokine antibody arrays and label‐free quantitative proteomics analysis were used to compare the differences between hypoxic CM and normoxic CM. Injection of normoxic CM significantly reduced the infarct area and improved neurological recovery after stroke compared with administering DMEM. These outcomes may be associated with the attenuation of apoptosis and promotion of angiogenesis. Hypoxic preconditioning significantly enhanced these therapeutic effects. Fourteen proteins were significantly increased in hypoxic CM compared with normoxic CM as measured by cytokine arrays. The label‐free quantitative proteomics analysis revealed 163 proteins that were differentially expressed between the two groups, including 107 upregulated proteins and 56 downregulated proteins. Collectively, our results demonstrate that hypoxic CM protected brain tissue from ischemic injury and promoted functional recovery after stroke in rats and that hypoxic CM may be the basis of a potential therapy for stroke patients.
Conditioned medium constitutes a therapeutic effect on stroke. Paracrine actions of bone marrow mesenchymal stromal cell are enhanced by hypoxic preconditioning. Apoptosis and neovascularization are involved in this beneficial effect.
RACK1 is upregulated in the various types of human cancers, and considered to play a role in the development and progression of human cancer. However, the role and mechanism of RACK in the colon ...cancer are poorly understood. In this study, we detected RACK1 expression in 63 normal colonic mucosa, 60 colonic inflammatory polyps, 60 colonic adenomas, 180 colon adenocarcinomas, and 40 lymph node metastases by immunohistochemistry, and observed that RACK1 expression was progressively elevated in the carcinogenic process of human colonic epithelium, and RACK1 expressional levels were positively correlated with the malignant degree and lymph node metastasis of colon cancers, and negatively correlated with the patient survival. With a combination of loss-of-function and gain-of-function approaches, we observed that RACK1 promoted colon cancer cell proliferation, inhibited colon cancer cell apoptosis, and enhanced the anchorage-independent and xenograft growth of colon cancer cells. Moreover, we found that RACK1-induced autophagy of colon cancer cells; RACK1-induced autophagy promoted colon cancer cell proliferation and inhibited colon cancer cell apoptosis. Our data suggest that RACK1 acts as an oncogene in colon cancer, and RACK1-induced autophagy promotes proliferation and survival of colon cancer, highlighting the therapeutic potential of autophagy inhibitor in the colon cancer with high RACK1 expression.
Overexpression of ANXA1 and EphA2 has been linked to various cancers and both proteins have attracted considerable attention for the development of new anticancer drugs. Here we report that ANXA1 ...competes with Cbl for binding EphA2 and increases its stability by inhibiting Cbl-mediated EphA2 ubiquitination and degradation in nasopharyngeal carcinoma (NPC). Binding of ANXA1 to EphA2 promoted NPC cell growth and metastasis
and
by elevating EphA2 levels and increasing activity of EphA2 oncogenic signaling (pS897-EphA2). Expression of ANXA1 and EphA2 was positively correlated and both were significantly higher in NPC tissues than in the normal nasopharyngeal epithelial tissues. Patients with high expression of both proteins presented poorer disease-free survival and overall survival relative to patients with high expression of one protein alone. Furthermore, amino acid residues 20-30aa and 28-30aa of the ANXA1 N-terminus bound EphA2. An 11 amino acid-long ANXA1-derived peptide (EYVQTVKSSKG) was developed on the basis of this N-terminal region, which disrupted the connection of ANXA1 with EphA2, successfully downregulating EphA2 expression and dramatically suppressing NPC cell oncogenicity
and in mice. These findings suggest that ANXA1 promotes NPC growth and metastasis via binding and stabilization of EphA2 and present a strategy for targeting EphA2 degradation and treating NPC with a peptide. This therapeutic strategy may also be extended to other cancers with high expression of both proteins. SIGNIFICANCE: These findings show that EphA2 is a potential target for NPC therapeutics and an ANXA1-derived peptide suppresses NPC growth and metastasis. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/20/4386/F1.large.jpg.
To maximum the activity of transition metal sulfides for hydrogen evolution reaction (HER), two strategies usually have been adopted including designing unique nanostructures and integrating other ...metal element. Herein, CoxSy/WS2 nanosheets supported on carbon cloth (CoxSy/WS2/CC) have been fabricated via a facile hydrothermal process. The cross-linked structures composed of CoxSy/WS2 nanosheets uniformly cover on the surface of CC, which may expose abundant active sites for HER and accelerate charge transfer rate. The molar ratio of CoxSy-incorporating has been investigated in detail. The molar ratio of W/Co = 1/3 (noted as CoxSy/WS2/CC-3) has been proved to have unique spherical CoxSy/WS2 nanostructure, which may further expose more active sites for HER. Electrochemical measurements demonstrate that CoxSy-incorporating can enhance HER activity and conductivity compared with WS2/CC. In addition, CoxSy/WS2/CC-3 exhibits the best HER activity, smallest charge transfer resistance and excellent stability than the counterparts, implying that the degree of CoxSy-incorporating may impact the HER activity of WS2. The mechanisms of CoxSy-incorporating on enhancing HER activity of WS2 have been discussed. It may offer a promising way to design transition metal sulfides-based electrocatalysts for HER by non-precious metal incorporating.
Display omitted
•Different CoxSy/WS2/CC samples have been fabricated via a facile hydrothermal process.•The molar ratio of CoxSy/WS2 has been investigated in detail.•The molar ratio of W/Co = 1/3 has been proved to have unique spherical nanostructure.•CoxSy/WS2/CC-3 exhibits the best HER activity and excellent stability.
Background
Preoperative evaluation of the consistency of pituitary macroadenomas is important for neurosurgeons to prepare the surgical plan.
Purpose
To evaluate the diagnostic performance of texture ...analysis (TA) of diffusion‐weighted imaging (DWI) at a standard b‐value (b = 1000 s/mm2) and a high b‐value (b = 2000 s/mm2) for their ability to assess the tumor consistency of pituitary macroadenomas.
Study Type
Retrospective.
Population/Subjects
Fifty patients with histologically confirmed pituitary macroadenomas were classified as soft (n = 37) or hard (n = 13) types.
Field Strength/Sequence
Coronal T2‐weighted imaging (T2WI), Readout Segmentation of Long Variable Echo‐trains (RESOLVE) DWI at b = 1000 s/mm2 and b = 2000 s/mm2 were acquired with 3.0T MRI.
Assessment
The corresponding apparent diffusion coefficient (ADC) maps (ADC1000 and ADC2000) were registered to T2WI. Regions of interest (ROIs) were manually drawn along the solid part of the tumor from the coregistered T2WI‐ADC images. The texture parameters from T2WI, ADC1000, and ADC2000 were acquired.
Statistical Tests
The texture parameters were compared between the two types by using unpaired Student's t‐test. Receiver operating characteristic (ROC) curves and logistic regression analyses were used to assess their diagnostic performance.
Results
Significant differences in TA parameters of ADC1000 and ADC2000 were observed between soft and hard types (P < 0.05 for all), whereas the TA of T2WI resulted in no significant difference (P > 0.05 for all). TA of ADC2000 provided a superior diagnostic performance compared with that of ADC1000 (P = 0.038). A combination of mean value and entropy of ADC2000 yielded an AUC, a sensitivity, and a specificity of 0.911, 78.4% and 92.3%, respectively.
Data Conclusion
TA of ADC values were useful for assessing the tumor consistency of pituitary macroadenomas. ADC2000 may facilitate better type discrimination.
Level of Evidence: 3
Technical Efficacy Stage: 2
J. Magn. Reson. Imaging 2020;51:1507–1513.
Background
The prognostic significance of hyperperfusion after reperfusion therapy in patients with acute ischemic stroke (AIS) remains controversial.
Purpose
To investigate the clinical factors ...associated with hyperperfusion, and the 90‐day prognostic value of hyperperfusion after mechanical thrombectomy in AIS patients.
Study Type
Retrospective.
Population/Subjects
Fifty‐four AIS patients who underwent mechanical thrombectomy.
Field Strength/Sequence
Time‐of‐flight MR angiography, pulsed arterial spin labeling (ASL), diffusion‐weighted imaging (DWI), and susceptibility‐weighted imaging were performed at 3.0T within 1 week after thrombectomy.
Assessment
Clinical factors including demographics, risk factors, stroke and treatment characteristics were collected and assessed. Hyperperfusion on ASL was defined as a focal increased cerebral blood flow on the affected side ≥130% of its mirror counterpart. Good clinical outcome at 90 days was defined as modified Rankin Scale score of 0–2.
Statistical Tests
The interrater agreement was assessed using Cohen's kappa or the intraclass correlation coefficient. The relationship between hyperperfusion and clinical factors were analyzed by appropriate univariate statistics. Predictors of 90‐day functional outcome were assessed by univariate analyses followed by multivariate logistic regression analysis and receiver‐operating‐characteristic curves.
Results
Thirty‐six (66.7%) patients developed hyperperfusion on ASL after thrombectomy. Hyperperfusion was significantly correlated with successful recanalization (P < 0.05) and improvement of National Institutes of Health Stroke Scale scores at 24 hours (NIHSS24h) (P < 0.05). A higher incidence of hemorrhage transformation was observed in patients with hyperperfusion than those without (63.9% vs. 50.0%), but no significant difference was found (P = 0.327). NIHSS24h (odds ratio OR, 0.75, 95% confidence interval CI 0.62–0.91, P < 0.05), lesion volume on diffusion‐weighted imaging (OR, 0.97, 95% CI 0.95–1.00, P < 0.05), and hyperperfusion on ASL (OR, 9.8, 95% CI 1.7–55.3, P < 0.05) were independent variables for predicting good functional outcomes.
Data Conclusion
Hyperperfusion on ASL correlated with successful recanalization and may be an independent prognostic marker for good neurological outcomes at 90 days in AIS patients after mechanical thrombectomy.
Level of Evidence
4
Technical Efficacy Stage
2
EphA2 is an important oncogenic protein and emerging drug target, but the oncogenic role and mechanism of ligand-independent phosphorylation of EphA2 at tyrosine 772 (pY772-EphA2) is unclear. In this ...study, we established nasopharyngeal carcinoma (NPC) cell lines with stable expression of exogenous EphA2 and EphA2-Y772A (phosphorylation inactivation) using endogenous EphA2-knockdown cells, and observed that pY772A EphA2 was responsible for EphA2-promoting NPC cell proliferation and anchorage-independent and in vivo growth in mice. Mechanistically, EphA2-Y772A mediated EphA2-activating Shp2/Erk-1/2 signaling pathway in the NPC cells, and Gab1 (Grb2-associated binder 1) and Grb2 (growth factor receptor-bound protein 2) were involved in pY772-EphA2 activating this signaling pathway. Our results further showed that Shp2/Erk-1/2 signaling mediated pY772-EphA2-promoting NPC cell proliferation and anchorage-independent growth. Moreover, we observed that EphA2 tyrosine kinase inhibitor ALW-II-41-27 inhibited pY772-EphA2 and EphA2-Y772A decreased the inhibitory effect of ALW-II-41-27 on NPC cell proliferation. Collectively, our results demonstrate that pY772-EphA2 is responsible for EphA2-dependent NPC cell growth in vitro and in vivo by activating Shp2/Erk-1/2 signaling pathway, and is a pharmacologic target of ALW-II-41-27, suggesting that pY772-EphA2 can serve as a therapeutic target in NPC and perhaps in other cancers.
PDF
