The transcription factor KLF14 regulates macrophage glycolysis and immune function by inhibiting HK2 in sepsis

Sepsis is a heterogeneous syndrome induced by a dysregulated host response to infection. Glycolysis plays a role in maintaining the immune function of macrophages, which is crucial for severely septic patients. However, how the pathways that link glycolysis and macrophages are regulated is still largely unknown. Here, we provide evidence to support the function of KLF14, a novel Krüppel-like transcription factor, in the regulation of glycolysis and the immune function of macrophages during sepsis. KLF14 deletion led to significantly increased mortality in lethal models of murine endotoxemia and sepsis. Mechanistically, KLF14 decreased glycolysis and the secretion of inflammatory cytokines by macrophages by inhibiting the transcription of HK2. In addition, we confirmed that the expression of KLF14 was upregulated in septic patients. Furthermore, pharmacological activation of KLF14 conferred protection against sepsis in mice. These findings uncover a key role of KLF14 in modulating the inflammatory signaling pathway and shed light on the development of KLF14-targeted therapeutics for sepsis.

Anticancer Activity of Ω-6 Fatty Acids through Increased 4-HNE in Breast Cancer Cells

Her2-amplified breast cancers resistant to available Her2-targeted therapeutics continue to be a challenge in breast cancer therapy. Dox is the mainstay of chemotherapy of all types of breast cancer, but its usefulness is limited by cumulative cardiotoxicity. Because oxidative stress caused by dox generates the pro-apoptotic Ω-6 PUFA metabolite 4-hydroxynonenal (4-HNE), we surmised that Ω-6 PUFAs would increase the effectiveness of dox chemotherapy. Since the mercapturic acid pathway enzyme RALBP1 (also known as RLIP76 or Rlip) that limits cellular accumulation of 4-HNE also mediates dox resistance, the combination of Ω-6 PUFAs and Rlip depletion could synergistically improve the efficacy of dox. Thus, we studied the effects of the Ω-6 PUFA arachidonic acid (AA) and Rlip knockdown on the antineoplastic activity of dox towards Her2-amplified breast cancer cell lines SK-BR-3, which is sensitive to Her2 inhibitors, and AU565, which is resistant. AA increased lipid peroxidation, 4-HNE generation, apoptosis, cellular dox concentration and dox cytotoxicity in both cell lines while sparing cultured immortalized cardiomyocyte cells. The known functions of Rlip including clathrin-dependent endocytosis and dox efflux were inhibited by AA. Our results support a model in which 4-HNE generated by AA overwhelms the capacity of Rlip to defend against apoptosis caused by dox or 4-HNE. We propose that Ω-6 PUFA supplementation could improve the efficacy of dox or Rlip inhibitors for treating Her2-amplified breast cancer.

Cdk5 drives formation of heterogeneous pancreatic neuroendocrine tumors

Pancreatic neuroendocrine tumors (PanNETs) are a heterogeneous population of neoplasms that arise from hormone-secreting islet cells of the pancreas and have increased markedly in incidence over the past four decades. Non-functional PanNETs, which occur more frequently than hormone-secreting tumors, are often not diagnosed until later stages of tumor development and have poorer prognoses. Development of successful therapeutics for PanNETs has been slow, partially due to a lack of diverse animal models for pre-clinical testing. Here, we report development of an inducible, conditional mouse model of PanNETs by using a bi-transgenic system for regulated expression of the aberrant activator of Cdk5, p25, specifically in β-islet cells. This model produces a heterogeneous population of PanNETs that includes a subgroup of well-differentiated, non-functional tumors. Production of these tumors demonstrates the causative potential of aberrantly active Cdk5 for generation of PanNETs. Further, we show that human PanNETs express Cdk5 pathway components, are dependent on Cdk5 for growth, and share genetic and transcriptional overlap with the INS-p25OE model. The utility of this model is enhanced by the ability to form tumor-derived allografts. This new model of PanNETs will facilitate molecular delineation of Cdk5-dependent PanNETs and the development of new targeted therapeutics.