Post-translational modification of CDK1-STAT3 signaling by fisetin suppresses pancreatic cancer stem cell properties.

BACKGROUND: Pancreatic cancer stem cells (CSCs) promote pancreatic ductal adenocarcinoma (PDAC) tumorigenesis and chemoresistance. Cyclin-dependent kinase 1 (CDK1) plays an important role in tumor initiation in other tumors, but the function of CDK1 in PDAC remains unclear. Fisetin is a bioactive flavonoid with anti-tumor properties in multiple tumors, while its function in CSCs remains elusive. RESULTS: In this study, we demonstrated that CDK1 was correlated with prognosis and was highly expressed in pancreatic cancer tissue and gemcitabine-resistant cells. Silencing CDK1 impaired tumor stemness and reduced a subset of CSCs. We found that fisetin blocked the kinase pocket domain of CDK1 and inhibited pancreatic CSC characteristics. Using acetylation proteomics analysis and phosphorylation array assay, we confirmed that fisetin reduced CDK1 expression and increased CDK1 acetylation at lysine 33 (K33), which resulted in the suppression of CDK1 phosphorylation. Silencing CDK1 or STAT3 suppressed tumor stemness properties, while overexpressing CDK1 or STAT3 showed the opposite effect. Mutation or acetylation of CDK1 at K33 weakened STAT3 phosphorylation at Y705, impairing the expression of stem-related genes and pancreatic cancer stemness. In addition, lack of histone deacetylase 3 (HDAC3), which deacetylates CDK1, contributed to weakening STAT3 phosphorylation by regulating the post-translational modification of CDK1, thereby decreasing the stemness of PDAC. Moreover, our results revealed that fisetin enhanced the effect of gemcitabine through eliminating a subpopulation of pancreatic CSCs by inhibiting the CDK1-STAT3 axis in vitro and in vivo. CONCLUSION: Our findings highlight the role of post-translational modifications of CDK1-STAT3 signaling in maintaining cancer stemness of PDAC, and indicated that targeting the CDK1-STAT3 axis with inhibitors such as fisetin is a potential therapeutic strategy to diminish drug resistance and eliminate PDAC.

Sirtuin4 impacts mitochondrial homeostasis in pancreatic cancer cells by reducing the stability of AlkB homolog 1 via deacetylation of the HRD1-SEL1L complex.

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor with a poor prognosis. As a tumor inhibitor, the specific tumor suppressor mechanism of Sirtuin4(SIRT4) in PDAC remains elusive. In this study, SIRT4 was found to inhibit PDAC by impacting mitochondrial homeostasis. SIRT4 deacetylated lysine 547 of SEL1L and increased the protein level of an E3 ubiquitin ligase HRD1. As a central member of ER-associated protein degradation (ERAD), HRD1-SEL1L complex is recently reported to regulate the mitochondria, though the mechanism is not fully delineated. Here, we found the increase in SEL1L-HRD1 complex decreased the stability of a mitochondrial protein, ALKBH1. Downregulation of ALKBH1 subsequently blocked the transcription of mitochondrial DNA-coded genes, and resulted in mitochondrial damage. Lastly, a putative SIRT4 stimulator, Entinostat, was identified, which upregulated the expression of SIRT4 and effectively inhibited pancreatic cancer in vivo and in vitro.

Mitigation of Lost Circulation in Oil-Based Drilling Fluids Using Oil Absorbent Polymers.

In order to mitigate the loss circulation of oil-based drilling fluids (OBDFs), an oil-absorbent polymer (OAP) composed by methylmethacrylate (MMA), butyl acrylate (BA), and hexadecyl methacrylate (HMA) was synthesized by suspension polymerization and characterized by Fourier transform infrared spectroscopy (FT-IR), thermogravimetric analysis (TGA) and scanning electronic microscopy (SEM). The oil-absorptive capacity of OAP under different solvents was measured as the function of temperature and time. The effect of the OAP on the rheological and filtration properties of OBDFs was initially evaluated, and then the sealing property of OAP particles as lost circulation materials (LCMs) was examined by a high-temperature and high-pressure (HTHP) filtration test, a sand bed filtration test, a permeable plugging test, and a fracture sealing testing. The test results indicated that the addition of OAP had relatively little influence on the rheological properties of OBDF at content lower than 1.5 w/v % but increased the fluid viscosity remarkably at content higher than 3 w/v %. It could reduce the HTHP filtration and improve the sealing capacity of OBDF significantly. In the sealing treatment, after addition into the OBDF, the OAP particles could absorb oil accompanied with volume enlargement, which led to the increase of the fluid viscosity and slowing down of the fluid loss speed. The swelled and deformable OAP particles could be squeezed into the micro-fractures with self-adoption and seal the loss channel. More important, fluid loss was dramatically reduced when OAP particles were combined with other conventional LCMs by a synergistic effect.