The RAS RAF MEK ERK pathway also known as the

The RAS/RAF/MEK/ERK pathway (also known as the MAPK/ERK pathway) is one of the most important signaling pathways in PDAC. Activation of the MAPK/ERK pathway promotes PDAC growth and apoptosis resistance in response to gemcitabine [43,44]. We previously demonstrated that inhibition of GPX4 can overcome gemcitabine resistance via induction of ferroptosis in PDAC Kaempferol-3-rutinoside [45]. We now demonstrated that activation of the MAPK/ERK pathway is required for erastin-induced STAT3 activation and subsequent ferroptosis in PDAC cells. Our findings are generally consistent with those from previous studies showing that ERK is an upstream kinase for STAT3 activation in response to various stressors [[46], [47], [48]]. In addition to RAS mutation-dependent ferroptosis, RAS mutation-independent ferroptosis also affects the anticancer activity of erastin [28]. The functional interplay between mutant and wild type RAS in control of STAT3 activation in ferroptosis remains to be further explored. Notably, we have characterized the mechanism of action of STAT3 in the context of our current understanding of the interplay between ferroptosis and lysosomal cell death. Lysosomes contain hydrolases such as the cathepsin family for the degradation and recycling of essential nutrients to maintain homeostasis within cells through multiple ways, including autophagy [49]. Lysosomal cell death is mainly carried out by cathepsin and can be induced by iron accumulation, oxidative injury, and autophagic cell death [36,37,50,51]. The original study shows that ferroptosis is different from lysosomal cell death and autophagy in HT1080 cells [20]. In contrast, increasing evidence has demonstrated that increased autophagy and lysosomal activity are involved in the induction of ferroptosis [[52], [53], [54], [55]]. We previously demonstrated that autophagy promotes ferroptosis by degradation of ferritin or inhibition of system Xc− activity [52,56]. In this study, we further demonstrated that STAT3-meidated cathepsin B expression is required for ferroptosis in PDAC cells via induction of lysosomal cell death. In addition, activation of STAT3 promotes lysosomal-mediated cell death in mice during mammary gland involution [15,16]. Thus, STAT3 seems to be an important transcription factor for lysosomal cell death in vitro and in vivo. In conclusion, our data suggest that ferroptosis is a lysosomal cell death process. This process at least requires activation of STAT3-mediated cathepsin B expression. Further understanding of the interplay between ferroptosis, lysosomal cell death, and autophagy will likely yield new insights into the molecular mechanism of regulated cell death [57].
Conflicts of interest
Acknowledgments We thank Christine Burr (Department of Surgery, University of Pittsburgh) for her critical reading of the manuscript. This work was supported by grants from the US National Institutes of Health (R01GM115366, R01CA160417, and R01CA211070), the Natural Science Foundation of Guangdong Province (2016A030308011), the Natural Science Foundation of Jilin Province (20160101062JC), the American Cancer Society (Research Scholar Grant RSG-16-014-01-CDD), the National Natural Science Foundation of China (31671435, 81772508, 30870355, and 81370497), Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (2017), Lin He's Academician Workstation of New Medicine and Clinical Translation (2017), International Scientific and Technology Cooperation Program of China (2015DFA31490), and the Health Foundation of Finance Department of Jilin Province (sczsy201516).
Main Text Cell death is an essential biological process for physiological growth and development. Deregulation of cell death plays a fundamental role in many human diseases including cancer. Apoptosis, necroptosis, autophagy, and ferroptosis are mechanisms of cell death by activating specific signaling pathways. While these are distinct pathways, they may have overlapping and interconnected processes that can be activated simultaneously and operate in parallel (Chen et al., 2018). In the event of cell death by any one of these means, the debris needs to be cleared by macrophages and other cells by efferocytosis and other processes. There is reasonable evidence to suggest that polyunsaturated fatty acids (PUFAs), such as arachidonic acid (AA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and their anti-inflammatory products (lipoxinA4 [LXA4], resolvins, protectins, and maresins) enhance while monounsaturated fatty acids interfere with efferocytosis.