Intestinal ischemia–reperfusion (I/R) is a common clinical problem that occurs during various clinical pathological processes. Excessive apoptosis has an indispensable role in intestinal I/R injury. Tumor necrosis factor receptor-associated factor 2 (TRAF2) and PKC ζ have an essential role in apoptosis. Here, we aimed to investigate the effects of PKC ζ and TRAF2 and to explore the correlation between PKC ζ and TRAF2 in intestinal I/R injury. Mice were subjected to intestinal I/R injury in vivo . In vitro experiments were conducted by treating Caco-2 cells with hypoxia/reoxygenation (H/R) stimulation to simulate intestinal I/R. Intestinal tissue samples and Caco-2 cells were examined using various approaches. Intestinal I/R induced the membrane translocation and phosphorylation of PKC ζ . Pretreatment with the PKC ζ activator phosphatidylcholine remarkably attenuated gut injury by suppressing apoptosis. H/R induced PKC ζ to combine with TRAF2, which was phosphorylated by PKC ζ at Ser 55 , but not at Ser 11 , under intestinal I/R or H/R conditions. In addition, TRAF2 Ser 55 phosphorylation increased cell survival by inhibiting cell apoptosis in the H/R model. Mechanistically, TRAF2 Ser 55 phosphorylation promoted NF- κ B activation but suppressed c-Jun activation in Caco-2 cells under H/R conditions. The results of this study demonstrate that the PKC ζ /TRAF2 pathway represents a novel protective mechanism against intestinal I/R injury. Therefore, the PKC ζ /TRAF2 pathway is a novel target for potential treatments of intestinal I/R injury-related diseases.
Over the past four decades, efforts to improve the prognosis of pancreatic cancer have yielded limited progress, largely due to the complex genetic mutations, a desmoplastic tumor microenvironment, and the rapid metabolic rewiring that enables pancreatic cancer cells to adapt to cellular stress. Recent studies have demonstrated the critical reliance of pancreatic cancer cells on autophagy for survival, fitness, and the development of resistance to various clinical therapies. These findings position autophagy as a potential therapeutic vulnerability for the development of novel neoadjuvant treatments. However, conventional autophagy inhibition often leads to the accumulation of p62, which activates p62-dependent pathways that promote tumor growth and metastasis, thereby limiting the efficacy of autophagy-targeting therapies. In this study, we demonstrate that the atypical protein kinase C isoform zeta (PKCζ) plays a pivotal role in maintaining intracellular homeostasis in pancreatic ductal adenocarcinoma (PDAC) cells. Inhibition of PKCζ downregulates BCL-2-associated athanogene 3 (BAG3), reduces the expression of key autophagy-related proteins, autophagy related 5 (ATG5) and Beclin-1, and attenuates autophagic flux. Notably, PKCζ-mediated autophagy suppression does not result in p62 accumulation, circumventing the pro-tumorigenic effects associated with conventional autophagy inhibition. Furthermore, PKCζ inhibition enhances the anti-tumor efficacy of other chemotherapeutic agents, such as mitogen-activated protein kinase kinase (MEK) inhibitors, in PDAC. These findings identify PKCζ as a promising therapeutic target and provide a foundation for the development of innovative treatment strategies for pancreatic cancer.
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