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  • br Acknowledgements This work was in part supported by

    2022-01-25


    Acknowledgements This work was in part supported by the FöFoLe program by Ludwig-Maximilians-Universität München (to T.S.), the Deutsche Forschungsgemeinschaft (DFG) CO 291/5-2, the Human Frontier Science Program (HFSP) RGP0013, the Helmholtz Validation Funds (Helmholtz Association of German Research Centres), the German Federal Ministry of Education and Research (BMBF) through the Joint Project Modelling ALS Disease In Vitro (MAIV, 01EK1611B) and the VIP+ program NEUROPROTEKT (03VP04260).
    Introduction Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and has the universal mutations in the proto-oncogene K-RAS [1]. In the USA, PDAC accounts for about 3% of all cancers and about 7% of all cancer deaths [2]. The five-year and one-year survival rates for PDAC patients are 5–7% and less than 20%, respectively [2]. For PDAC that has not spread to distant sites, surgery is considered the primary treatment. Most PDAC patients are diagnosed at a late stage and radical pancreatic resection is not possible. Gemcitabine-based chemotherapy is currently the leading therapy for all stages of PDAC [3]. However, cell signaling pathway alterations, metabolic reprogramming, and an immunosuppressive microenvironment result in resistance to conventional chemotherapy, including gemcitabine [[4], [5], [6], [7]]. STAT3 (signal transducer and activator of transcription 3) is a signaling molecule for many cytokines and growth factor receptors and plays an important role in tumor biology [8]. Basic and clinical studies have found that STAT3 is constitutively activated in PDAC and possesses oncogenic potential in tumorigenesis and anti-apoptotic functions in therapy [[9], [10], [11], [12]]. After activation, STAT3 translocates from the cytosol to the nucleus where it controls W 54011 of several genes involved in the regulation of multiple cellular processes, including cell survival and cell death [[13], [14], [15], [16], [17]]. Thus, STAT3 is an important therapeutic target for human cancers, including PDAC [8]. Ferroptosis is a multi-step regulated cell death process from iron accumulation and lipid peroxidation [18,19]. This non-apoptotic form of cell death was first observed in RAS mutated cells in response to the small molecule erastin, which can inhibit the cystine/glutamate transporter system Xc−, leading to cysteine starvation, glutathione depletion, and consequently, oxidative death [20]. In addition to inhibition of system Xc− activity, impaired antioxidant GPX4 (glutathione peroxidase 4) enzyme functions [21,22] or NRF2 (nuclear factor erythroid 2-related factor 2)-antioxidant response [23,24] also can induce ferroptosis in vitro or in vivo. However, the molecular mechanisms of signal transduction in ferroptosis remain obscure.
    Methods
    Results
    Discussion Oxidative stress is essentially an imbalance between the production of reactive oxygen species and a biological system's ability to counteract or detoxify their harmful effects through neutralization by antioxidants [38]. Oxidative stress can cause various forms of cell death through different signal transduction mechanisms [39]. GSH, the major antioxidant in mammalian cells, is under tight homeostatic control both intracellularly and extracellularly. The system Xc−-mediated GSH production was recently described as the most upstream negative regulator of ferroptosis [18,19]. We found that the system Xc− inhibitors erastin and sorafenib play different roles in the regulation of STAT3 activation. Unlike erastin induced STAT3 activation, sorafenib inhibited STAT3 activation. These findings are consistent with those from previous studies showing that sorafenib inhibits STAT3 activation to enhance the anticancer activity of apoptotic stimuli in PDAC, neuroblastoma, or liver cancer cells [[40], [41], [42]]. In addition to system Xc−, erastin has other binding targets such as voltage-dependent anion channel (VDAC) in mitochondria [29]. It remains unknown whether VDAC-mediated electrical control of mitochondrial outer membrane permeability is required for erastin-induced STAT3 activation, although STAT3 also plays a role in mitochondrial stress.