How pancreatic cancer survives ferroptosis?
Pancreatic ductal adenocarcinoma (PDAC) tumors harboring KRAS mutations exhibit relative resistance to iron-dependent form of cell death, ferroptosis, compared with other tumor types but the mechanisms remain unclear.
The researchers reveal that hypoxia and pancreatic tumor interstitial fluid cooperate to suppress ferroptosis in pancreatic cancer through HIF-2 activity.
HIF-2 enables tumor survival by regulating glutathione metabolism through upregulating the expression of both components of the system Xc− cystine transporter and transsulfuration pathway enzymes CBS and CTH to increase intracellular cysteine levels.
HIF-2 also induces the Parkin mitophagy factor and suppresses mitochondrial function and reactive oxygen species (ROS) generation and thus survives metabolically hostile environments, defining a tissue-specific role in pancreatic ductal adenocarcinoma.
https://www.cell.com/molecular-cell/fulltext/S1097-2765(26)00163-2
