Helicobacter pylori CagA-mediated ether lipid biosynthesis promotes ferroptosis susceptibility in gastric cancer

Abstract

Helicobacter pylori, particularly cytotoxin-associated gene A (CagA)-positive strains, plays a key role in the progression of gastric cancer (GC). Ferroptosis, associated with lethal lipid peroxidation, has emerged to play an important role in malignant and infectious diseases, but the role of CagA in ferroptosis in cancer cells has not been determined. Here, we report that CagA confers GC cells sensitivity to ferroptosis both in vitro and in vivo. Mechanistically, CagA promotes the synthesis of polyunsaturated ether phospholipids (PUFA-ePLs), which is mediated by increased expression of alkylglycerone phosphate synthase (AGPS) and 1-acylglycerol-3-phosphate O-acyltransferase 3 (AGPAT3), leading to susceptibility to ferroptosis. This susceptibility is mediated by activation of the MEK/ERK/SRF pathway. SRF is a crucial transcription factor that increases AGPS transcription by binding to the AGPS promoter region. Moreover, the results demonstrated that CagA-positive cells are more sensitive to apatinib than are CagA-negative cells, suggesting that detecting the H. pylori CagA status may aid patient stratification for treatment with apatinib.

Unlocking ferroptosis: CagA’s role in gastric cancer cells

Gastric cancer, a major cause of cancer death globally, is often associated with chronic infection by a bacterium named Helicobacter pylori. A specific strain of H. pylori that produces a protein named CagA is particularly harmful, as it can cause severe stomach diseases, including cancer. However, the connection between CagA and a kind of cell death known as ferroptosis in gastric cancer cells was unclear. In this research, scientists discovered that CagA boosts the production of certain fats in cells, making them more prone to ferroptosis. The study was an experiment involving both cell cultures and animal models. The researchers concluded that targeting the pathway influenced by CagA could be a new strategy for treating gastric cancer, especially in patients infected with CagA-positive H. pylori strains.

This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.