Background Cisplatin is a commonly used nephrotoxic drug and can cause acute kidney injury (AKI). In the present study, isobaric tags for relative and absolute quantification (iTRAQ) and parallel reaction monitoring (PRM)-based comparative proteomics were used to analyze differentially expressed proteins (DEPs) to determine the key molecular mechanism in mice with cisplatin-induced AKI in the presence or absence of SIS3, a specific p-smad3 inhibitor, intervention. Methods The cisplatin-induced AKI mouse model was established and treated with SIS3. We used iTRAQ to search for DEPs, PRM to verify key DEPs and combined Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) for bioinformatics analysis. We then assessed lipid deposition, malondialdehyde (MDA) and reactive oxygen species (ROS) and detected the expression of SREBF1, SCD1, CPT1A, PPARα and NDRG1 in vitro. Results Proteomic analysis showed that the identified DEPs were mainly enriched in energy metabolism pathways, especially in lipid metabolism. When SIS3 was applied to inhibit the phosphorylation of Smad3, the expression of NDRG1 and fatty acid oxidation key proteins CPT1A and PPARα increased, the expression of lipid synthesis related proteins SREBF1 and SCD1 decreased and the production of lipid droplets, MDA and ROS decreased. Conclusion SIS3 alleviates oxidative stress, reduces lipid accumulation and promotes fatty acid oxidation through NDRG1 in cisplatin-induced AKI. Our study provides a new candidate protein for elucidating the molecular mechanisms of fatty acid metabolism disorders in cisplatin-induced acute kidney injury.

Renal cell carcinoma (RCC) is a common malignant tumor in the world. Histologically, most of RCC is classified as clear cell renal cell carcinoma (ccRCC), which is the most prevalent subtype. The overall survival of patients with ccRCC is poor, thus it is urgent to further explore its mechanism and target. S-phase kinase-associated protein 2 (SKP2) is overexpressed in a variety of human cancers and is associated with poor prognosis by enhancing tumor progression. However, it is unclear whether or how SKP2 is involved in ccRCC progression. Here, we reported that overexpression of SKP2 enhanced cell proliferation of ccRCC, while SKP2 depletion exhibited the opposite effect. Bioinformatic analyses found that SKP2 was positively correlated with Aurora-A (Aur-A) in ccRCC. The protein and mRNA levels of SKP2 were elevated or reduced by Aur-A overexpression or silencing, respectively. It was further found that Aur-A caused an increase phosphorylation of FOXO3A, which is a negatively transcription factor for SKP2. Interestingly, SKP2 mediated ubiquitylation and degradation of FOXO3A depend on the kinase activity of Aur-A. The combination of Aur-A inhibitor MLN8237 and SKP2 inhibitor SZL P1-41 showed a synergistic tumor growth inhibition in vivo and in vitro of ccRCC models. Thus, our data reveal that Aurora-A/FOXO3A/SKP2 axis promotes tumor progression in ccRCC, and the double inhibition of SKP2 and Aur-A shows significant synergistic effect, which indicates a potential new therapeutic strategy for ccRCC.

Introduction. Platelet-to-lymphocyte ratio (PLR) is widely used as an inflammatory marker and is associated with poor prognosis in some diseases, such as cardiovascular diseases and malignancies. However, the association between the PLR and all-cause mortality in peritoneal dialysis (PD) patients is unclear. Methods. A total of 939 patients were enrolled. The X-tile program was performed to calculate the optimal cut-off values for the PLR, and the patients were divided into three groups according to the cut-off values: a low PLR group (< 108.33), medium PLR group (108.33 to 257.50), and high PLR group (> 257.50). Multivariate analysis was performed to assess the prognostic value of PLR. The primary end point was all-cause mortality. Results. Of the 939 patients, the mean age was 49.9 years, and 57% of the patients were male. During a median follow-up of 27.5 months (interquartile range, 13.6-41.6 months), 221 (23.5%) died, in whom 114 (51.6%) deaths were attributed to cardiovascular mortality. Patients in the high PLR group had a higher mortality rate than patients in the low PLR group (log rank = 13.75, P < .001). The 1-year and 3-year overall survival rates were 88.9% and 71.7% for patients in the high PLR group compared with 98.6% and 86.2% for patients in the low PLR group, respectively. Similarly, multivariate Cox regression analysis showed that the mortality rate was higher in the high PLR group than in the low PLR group (HR = 1.64, 95% CI: 1.02 to 2.63, P < .05). Conclusion. An increased PLR value was independently associated with all-cause mortality in PD patients.

SAG (Sensitive to Apoptosis Gene) and ROC1 (Regulator of Cullin-1) are two family members of the RING component of CRL (Cullin RING ligase). Both members are essential for growth and survival of several types of human cancer cells; their role in renal cell carcinoma (RCC), however, remains elusive. Here we reported that compared to adjacent normal tissues, both SAG and ROC1 are overexpressed in RCC, which is positively correlated with poor patient survival, particularly for SAG. Depletion of SAG or ROC1 inhibited growth and survival of RCC cells by inducing G2/M arrest, senescence, and apoptosis likely due to accumulation of WEE1, p21, p27, NOXA, and BIM. Interestingly, simultaneous BIM knockdown in RCC cells partially rescues growth suppression triggered by depletion of SAG, but not ROC1, suggesting a differential role of BIM. Collectively, our study provides the proof-of-concept evidence that RING components of CRL are attractive candidates for targeted therapy of RCC.

Background/Aims: CyclinG1 (CycG1) is frequently overexpressed in solid tumors and overexpression of CycG1 promotes cell survival upon paclitaxel exposure by inducing polyploidy. Whether and how CycG1 regulates polyploidization caused by small molecular targeted inhibitors remains unclear. Methods: Immunohistochemistry and immunoblotting were utilized to examine protein expression. Cell proliferation was measured by ATPlite assay, and cell cycle distribution and apoptosis were measured by flow cytometry and/or DNA fragmentation assays. Results: Overexpression of CycG1 in breast cancer cells caused apoptosis-resistant polyploidy upon treatment with Aurora kinase inhibitor, ZM447439 (ZM). Addition of ABT-263, a small-molecule BH3 mimetic, to ZM, produced a synergistic loss of cell viability with greater sustained tumor growth inhibition in breast cancer cell lines. Decrease of Mcl-1 and increase of NOXA caused by ZM treatment, were responsible for the synergy. Furthermore, CycG1 was highly expressed in Triple-Negative-Breast-Cancer patients treated with paclitaxel and was paralleled by decreased cell survival. Conclusion: CycG1 is a crucial factor in ZM-induced polyploidy resistance, and ABT-263/ZM combination hold therapeutic utility in the CycG1-amplified subset of breast cancer and CycG1, thus, is a promising target in breast cancer.