Abstract

Oncogenic KRas reprograms pancreatic ductal adenocarcinoma (PDAC) cells to states which are highly resistant to apoptosis. Thus, a major preclinical goal is to identify effective strategies for killing PDAC cells. Artesunate (ART) is an anti-malarial that specifically induces programmed cell death in different cancer cell types, in a manner initiated by reactive oxygen species (ROS)-generation. In this study we demonstrate that ART specifically induced ROS- and lysosomal iron-dependent cell death in PDAC cell lines. Highest cytotoxicity was obtained in PDAC cell lines with constitutively-active KRas, and ART did not affect non-neoplastic human pancreatic ductal epithelial (HPDE) cells. We determined that ART did not induce apoptosis or necroptosis. Instead, ART induced ferroptosis, a recently described mode of ROS- and iron-dependent programmed necrosis which can be activated in Ras-transformed cells. Co-treatment with the ferroptosis inhibitor ferrostatin-1 blocked ART-induced lipid peroxidation and cell death, and increased long-term cell survival and proliferation. Importantly, analysis of PDAC patient mRNA expression indicates a dependency on antioxidant homeostasis and increased sensitivity to free intracellular iron, both of which correlate with Ras-driven sensitivity to ferroptosis. Overall, our findings suggest that ART activation of ferroptosis is an effective, novel pathway for killing PDAC cells.

Highlights

  • Pancreatic ductal adenocarcinoma (PDAC) is an incurable form of cancer

  • We report that co-treatment with either the reactive oxygen species (ROS) scavenger trolox, the inhibitor of ferroptosis, ferrostatin-1, or the iron chelator deferoxamine block ART cytotoxicity, while loading lysosomes with ironsaturated holo-transferrin enhances ferroptotic PDAC cell death

  • The necroptosis inhibitor Nec-1s had no impact on cell death under any conditions. These findings demonstrate that erastin and ART activate ferroptosis in PDAC cell lines in an iron- and ROS-dependent manner, and that ART-induced ferroptosis is most efficient in mutationally-active KRas expressing PDAC cell lines while Fer-1 block of cell death is independent from KRas mutation status

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Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is an incurable form of cancer. PDAC is driven by constitutively-active KRas mutations [3, 4], which result in metabolic reprogramming [5,6,7] and resistance to apoptosis [8]. PDAC is highly resistant to death receptor and mitochondrial modes of apoptotic programmed cell death [8]. Death receptor activation is an important source of cancer-promoting inflammation signaling [9] and promotes metastasis [10]. The discovery of efficient strategies to kill pancreatic cancer cells remains an outstanding goal in programmed cell death (PCD) research, and considerable efforts are being made to identify general, as well as patient-specific, molecular targeting strategies [11, 12]

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