TY - JOUR
T1 - DUSP1 Blocks autophagy-dependent ferroptosis in pancreatic cancer
AU - Xie, Yangchun
AU - Kuang, Feimei
AU - Liu, Jiao
AU - Tang, Daolin
AU - Kang, Rui
N1 - Funding Information:
We thank Dave Primm (Department of Surgery, University of Texas Southwestern Medical Center) for his critical reading of the manuscript. Y.X. was supported the National Natural Science Foundation of China (81802476 and 81772508).
Publisher Copyright:
Copyright © 2020 The Chinese Medical Association, Published by Wolters Kluwer Health, Inc.
PY - 2020/9/1
Y1 - 2020/9/1
N2 - Ferroptosis is a oxidative damage-dependent form of regulated cell death that has become an emerging target for disease prevention and treatment. Here, we show that dual-specificity phosphatase 1 (DUSP1), a phosphatase playing multiple roles in stress-signaling pathways, is a new repressor of ferroptosis in human pancreatic cancer cells. Several classical ferroptosis activators (eg, erastin and RSL3) induce the expression of DUSP1, but not other members of DUSP, which depends on extracellular signal-regulated protein kinases 1 and 2 (ERK1/2). Moreover, shRNA-mediated DUSP1 knockdown increases the anticancer activity of ferroptosis activators in pancreatic cancer cells through activating lipid peroxidation in vitro and in vivo. Importantly, DUSP1-mediated autophagy is responsible for lipid peroxidation-mediated ferroptotic cell death. Thus, the DUSP1-related ferroptotic pathway may represent a potential target for therapeutic intervention in pancreatic cancer.
AB - Ferroptosis is a oxidative damage-dependent form of regulated cell death that has become an emerging target for disease prevention and treatment. Here, we show that dual-specificity phosphatase 1 (DUSP1), a phosphatase playing multiple roles in stress-signaling pathways, is a new repressor of ferroptosis in human pancreatic cancer cells. Several classical ferroptosis activators (eg, erastin and RSL3) induce the expression of DUSP1, but not other members of DUSP, which depends on extracellular signal-regulated protein kinases 1 and 2 (ERK1/2). Moreover, shRNA-mediated DUSP1 knockdown increases the anticancer activity of ferroptosis activators in pancreatic cancer cells through activating lipid peroxidation in vitro and in vivo. Importantly, DUSP1-mediated autophagy is responsible for lipid peroxidation-mediated ferroptotic cell death. Thus, the DUSP1-related ferroptotic pathway may represent a potential target for therapeutic intervention in pancreatic cancer.
KW - Dual-specificity phosphatase 1
KW - Ferroptosis
KW - Pancreatic cancer
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U2 - 10.1097/JP9.0000000000000054
DO - 10.1097/JP9.0000000000000054
M3 - Article
AN - SCOPUS:85089866970
SN - 2096-5664
VL - 3
SP - 154
EP - 160
JO - Journal of Pancreatology
JF - Journal of Pancreatology
IS - 3
ER -