Programmed cell death in Helicobacter pylori infection and related gastric cancer

Abstract

Programmed cell death (PCD) plays a crucial role in maintaining the normal structure and function of the digestive tract in the body. Infection with Helicobacter pylori (H. pylori) is an important factor leading to gastric damage, promoting the Correa cascade and accelerating the transition from gastritis to gastric cancer. Recent research has shown that several PCD signaling pathways are abnormally activated during H. pylori infection, and the dysfunction of PCD is thought to contribute to the development of gastric cancer and interfere with treatment. With the deepening of studies on H. pylori infection in terms of PCD, exploring the interaction mechanisms between H. pylori and the body in different PCD pathways may become an important research direction for the future treatment of H. pylori infection and H. pylori-related gastric cancer. In addition, biologically active compounds that can inhibit or induce PCD may serve as key elements for the treatment of this disease. In this review, we briefly describe the process of PCD, discuss the interaction between different PCD signaling pathways and the mechanisms of H. pylori infection or H. pylori-related gastric cancer, and summarize the active molecules that may play a therapeutic role in each PCD pathway during this process, with the expectation of providing a more comprehensive understanding of the role of PCD in H. pylori infection.

Keywords: Helicobacter pylori; gastric cancer; infection; programmed cell death; therapy.

Figure 1

Apoptosis and Necroptosis in H. pylori infection. In the intrinsic pathway of apoptosis, only BH3 proteins are upregulated after H. pylori infection. They interact with the BCL-2 proteins, which are essential for survival, and thus override the inhibition of BAX and BAK. As a result, BAX and BAK oligomerize, leading to MOMP. After its release into the cytoplasm, cytochrome c binds to Apaf-1, which activates the initiator caspases and induces apoptosis. VacA, which causes the translocation of BAX and increases cytochrome c, can also enhance apoptosis. BID is one of the pure BH3 proteins. It can be cleaved by activated caspase-8 and releases BAX and BAK to activate intrinsic apoptosis via the MOMP pathway. In the extrinsic pathway, H. pylori promotes the formation of pAbIT735 via the type IV secretion system (T4SS), thereby attenuating caspase-8-dependent cell apoptosis. In necroptosis, infection with H. pylori leads to an increase in the key factor RIPK3, which promotes the occurrence of inflammatory reactions. VacA also triggers necroptosis and releases considerable amounts of inflammatory mediators.

Figure 2

Apoptosis in chronic H. pylori infection. In chronic infection, H. pylori can trigger dysregulation of the BCL-2 system and downregulate apoptosis. H. pylori also leads to chronic inflammation, triggers oxidative stress and inhibits apoptosis. CagA, the virulence factor released by H. pylori, can regulate the activation of PI3K and AKT. AKT-dependent phosphorylation of caspase-9 attenuates apoptosis. All these dysregulations of apoptosis in chronic infection lead to the formation of a tumor microenvironment and ultimately contribute to the development of gastric cancer.

Figure 3

Pyroptosis and ferroptosis in H. pylori infection. In pyroptosis, H. pylori and its virulence factors (e.g. CagA, VacA, UreB) trigger the inflammatory cascade of NLRP3, which leads to the activation of caspase-1. Caspase-1 cleaves pro-IL-1β to generate its active form and also targets GSDMD, leading to recruitment of the N-terminal fragment of GSDMD to the plasma membrane. This leads to pore formation and the subsequent release of inflammatory factors. Upon ferroptosis, H. pylori and its OMVs upregulate Solute Carrier Family 3 Member 2 (SLC3A2) to attenuate ferroptosis, while repressing lysophosphatidylcholine acyltransferase 3 (LPCAT3) and downregulating transferrin receptor 1 (TfR1) to attenuate lipid peroxidation. H. pylori may also increase susceptibility to RAS-selective lethality 3 (RSL3)-induced ferroptosis by influencing associated genes.

Figure 4

Autophagy in H. pylori infection. In autophagy, bacteria can be used to form damaged pathogen-containing vesicles. Under the action of the Beclin1 complex and the ATG systems, autophagosomes are formed that cooperate with the lysosomes in the cell to complete autophagy. When infected with H. pylori, the bacterial toxin VacA can target mitochondria to inhibit mTORC1 to promote cell autophagy. CagA, another toxin factor secreted by H. pylori, can evade autophagic degradation and gradually reduce cell autophagy. These complex circumstances during H. pylori infection lead to dysregulation of autophagy.