Abstract
Pancreatic cancer is a devastating gastrointestinal cancer, characterized by late diagnosis, low treatment success rate, and poor survival prognosis. The most common pathological type of pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC), which is mainly driven by the K-Ras oncogene. Ferroptosis was originally described as Ras-dependent cell death, but is now defined as lipid peroxidation-mediated regulated necrosis, accompanied by excessive activation of the autophagy degradation pathway and limited membrane repair capacity. The impaired ferroptotic pathway is involved in many types of cancer, including PDAC. On the one hand, the chronic inflammation caused by ferroptotic damage contributes to the formation of K-Ras-driven PDAC. On the other hand, drug-induced ferroptosis is an emerging strategy to suppress tumor growth in established PDAC. In this mini-review, we outline the core process of ferroptosis, discuss the regulatory mechanism of ferroptosis in PDAC, and highlight some of the challenges of targeting ferroptosis in PDAC therapy.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the most common pathological type of pancreatic cancer, accounting for more than 90% of all pancreatic malignancies (Kleeff et al, 2016)
The KRAS gene is mutated in approximately 85–90% of PDAC and is the main driver of pancreatic tumorigenesis (Buscail et al, 2020)
As a conservative membrane repair mechanism, the calcium-dependent endosomal sorting complexes required for transport (ESCRT)-III pathway can be activated to separate damaged membranes in various cancer cells during ferroptosis (Dai et al, 2020b)
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the most common pathological type of pancreatic cancer, accounting for more than 90% of all pancreatic malignancies (Kleeff et al, 2016). Despite improvements in surgical techniques, chemotherapy regimens, and the introduction of neoadjuvant chemoradiotherapy or chemoimmunotherapy, PDAC still accounts for 3% of all cancers and 7% of all cancer deaths in the United States (Siegel et al, 2021). The poor outcomes of PDAC are mainly due to the late diagnosis of the disease and its resistance to treatments involving cell death. It is essential to understand the cell death machinery of PDAC and to develop new treatment strategies (Chen et al, 2021a). Recent studies have shown that inducing ferroptotic cell death may be an attractive therapy for various types of cancer, including PDAC (Su et al, 2020; Chen et al, 2021b; Shi et al, 2021)
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