Ferroptosis, necroptosis, and pyroptosis in the occurrence and development of ovarian cancer

Abstract

Ovarian cancer (OC) is one of the most common malignancies that causes death in women and is a heterogeneous disease with complex molecular and genetic changes. Because of the relatively high recurrence rate of OC, it is crucial to understand the associated mechanisms of drug resistance and to discover potential target for rational targeted therapy. Cell death is a genetically determined process. Active and orderly cell death is prevalent during the development of living organisms and plays a critical role in regulating life homeostasis. Ferroptosis, a novel type of cell death discovered in recent years, is distinct from apoptosis and necrosis and is mainly caused by the imbalance between the production and degradation of intracellular lipid reactive oxygen species triggered by increased iron content. Necroptosis is a regulated non-cysteine protease-dependent programmed cell necrosis, morphologically exhibiting the same features as necrosis and occurring via a unique mechanism of programmed cell death different from the apoptotic signaling pathway. Pyroptosis is a form of programmed cell death that is characterized by the formation of membrane pores and subsequent cell lysis as well as release of pro-inflammatory cell contents mediated by the abscisin family. Studies have shown that ferroptosis, necroptosis, and pyroptosis are involved in the development and progression of a variety of diseases, including tumors. In this review, we summarized the recent advances in ferroptosis, necroptosis, and pyroptosis in the occurrence, development, and therapeutic potential of OC.

Keywords: ferroptosis; malignant progression; necroptosis; ovarian cancer; pyroptosis.

Figure 1

Mechanisms of amino acids and lipid metabolism in ferroptosis. Cysteine can be transported into the cell, whereas glutamate can be transported out of the cell by the Xc-system. Cysteine can be used to synthesize glutathione to maintain the balance of the redox state, and it can also be synthesized through the transsulfurization pathway blocked by CARS. Glutamate can be converted to a-KG by transaminase or GLUD1 pathway and participate in TCA, thereby generating ROS. PUFAs derived from cell membranes can be catalyzed by ACSL4 and LPCAT to PUFA-PE, and PUFA-PE can be peroxidized by the LOX family. FSP1 and coenzyme Q also play an important role in the antioxidant system of coenzyme Q.

Figure 2

Mechanisms of iron metabolism in ferroptosis. Fe³⁺ can couple to transferrin and enter the intercellular milieu mediated by TfR1. Transferrin can be recycled and exported extracellularly and blocked by HSPB1. Fe³⁺ is reduced to Fe²⁺ by DMT1 in endosomes, and Fe²⁺ can be transported into the cytoplasm. Fe²⁺ can be released from ferritin through NCOA4-mediated ferritin phagocytosis, and part of Fe²⁺ can be exported outside the cell and oxidized by FPN. In addition, DOX can also induce ferroptosis. Cardiac output of DOX activates the Keap1/Nrf2 pathway, and Nrf2 further activates the downstream protein Hmox1 and prompts it to oxidize heme and release iron, leading to ferroptosis.

Figure 3

Potential mechanism of necroptosis. Necroptotic death may have evolved into the innate immune mechanism that complements apoptosis to eliminate pathogens. Necroptosis is affected by receptor interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like protein (MLKL).

Figure 4

Potential mechanism of pyroptosis. The molecular mechanisms of pyrolysis mainly include canonical and noncanonical signaling.