Osteoarthritis is one of the leading causes of pain and disability in the aged population due to articular cartilage damage. This warrants investigation of signaling mechanisms that could protect cartilage from degeneration and degradation. Here we show in a murine model of experimental osteoarthritis that YAP activation by transgenic overexpression or by deletion of its upstream inhibitory kinases Mst1/2 preserves articular cartilage integrity, whereas deletion of YAP in chondrocytes promotes cartilage disruption. Our work shows that YAP is both necessary and sufficient for the maintenance of cartilage homeostasis in osteoarthritis. Mechanistically, inflammatory cytokines, such as TNFα or IL-1β, trigger YAP/TAZ degradation through TAK1-mediated phosphorylation. Furthermore, YAP directly interacts with TAK1 and attenuates NF-κB signaling by inhibiting substrate accessibility of TAK1. Our study establishes a reciprocal antagonism between Hippo-YAP/TAZ and NF-κB signaling in regulating the induction of matrix-degrading enzyme expression and cartilage degradation during osteoarthritis pathogenesis.

YAP confers small cell lung cancer with the intratumoral heterogeneity and resistance to chemotherapy drugs.

Shear stress exerted by the blood stream modulates endothelial functions through altering gene expression. KLF2 and KLF4, the mechanosensitive transcription factors, are promoted by laminar flow to maintain endothelial homeostasis. However, how the expression of KLF2/4 is regulated by shear stress is poorly understood. Here, we showed that the activation of PIEZO1 upregulates the expression of KLF2/4 in endothelial cells. Mice with endothelial-specific deletion of Piezo1 exhibit reduced KLF2/4 expression in thoracic aorta and pulmonary vascular endothelial cells. Mechanistically, shear stress activates PIEZO1, which results in a calcium influx and subsequently activation of CaMKII. CaMKII interacts with and activates MEKK3 to promote MEKK3/MEK5/ERK5 signaling and ultimately induce the transcription of KLF2/4. Our data provide the molecular insight into how endothelial cells sense and convert mechanical stimuli into a biological response to promote KLF2/4 expression for the maintenance of endothelial function and homeostasis.

Our previous study revealed that PI3K/AKT/mTOR signaling was associated with SCLC radioresistance. SBC2 cells were used as primary radioresistance models, while H446 cells were continuously exposed to ionizing radiation (IR) to develop acquired radioresistance. Cell viability and apoptosis assays were used to investigate synergistic effects of BEZ235/GSK2126458 and IR in vitro, while immunoblotting, metabolite quantitative analysis and bioinformatic analyses were utilized to explore the underlying mechanism. Both genetically engineered mouse models (GEMM) and subcutaneous tumor models were used to confirm the synergistic effect in vivo. Key molecules of PI3K/AKT/mTOR signaling were upregulated after IR, which was correlated with primary radioresistance, and they were more expressed in acquired radioresistant cells. BEZ235/GSK2126458 effectively enhanced the cytotoxic effects of IR. BEZ235/GSK2126458 plus IR elevated γ-H2AX and p-Nrf2 expression, suggesting DNA and oxidative stress damage were intensified. Mechanistically, BEZ235/GSK2126458 plus IR significantly reduced the expression of G6PD protein, the rate-limiting enzyme of the pentose phosphate pathway (PPP). In detail, PI3K/mTOR inhibitors reinforced interaction between G6PD and HSPA8/HSC70, and G6PD was degraded by chaperone-mediated autophagy processes. Their metabolites (NADPH and R-5P) were decreased, and ROS levels were indirectly elevated, both of which exacerbated cell death. PI3K/AKT/mTOR signaling activator, insulin, enhanced SCLC radioresistance, while the synergistic effect of BEZ235/GSK2126458 and IR can be attenuated by N-acetylcysteine, and enhanced by 6-amino niacinamide. GEMM and allograft transplantation assays further confirmed their synergistic effect in vivo. This study provided insights into the connection between PI3K/AKT/mTOR signaling and the PPP underlying radioresistance and provided evidence of mechanisms supporting PI3K/mTOR inhibitors as possible therapeutic strategies to abrogate SCLC radioresistance.