Genome, Metabolism, or Immunity: Which Is the Primary Decider of Pancreatic Cancer Fate through Non-Apoptotic Cell Death?

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a solid tumor characterized by poor prognosis and resistance to treatment. Resistance to apoptosis, a cell death process, and anti-apoptotic mechanisms, are some of the hallmarks of cancer. Exploring non-apoptotic cell death mechanisms provides an opportunity to overcome apoptosis resistance in PDAC. Several recent studies evaluated ferroptosis, necroptosis, and pyroptosis as the non-apoptotic cell death processes in PDAC that play a crucial role in the prognosis and treatment of this disease. Ferroptosis, necroptosis, and pyroptosis play a crucial role in PDAC development via several signaling pathways, gene expression, and immunity regulation. This review summarizes the current understanding of how ferroptosis, necroptosis, and pyroptosis interact with signaling pathways, the genome, the immune system, the metabolism, and other factors in the prognosis and treatment of PDAC.

Keywords: apoptosis; ferroptosis; necroptosis; pancreatic ductal adenocarcinoma; pyroptosis.

Figure 1

Signaling pathways involved in ferroptosis. After entering, cystine via system XC⁻ antiporter GPX4 works as an antioxidant and reduces intracellular ROS. However, HSPA5 enhances GPX4 antioxidant activity by stabilizing this enzyme. HSP90 inhibits this antioxidant and subsequently increases ROS. On the one hand, ER enhances GPX4 via AFT4, facilitating HSPA5 expression. On the other hand, it facilitates PLOOH by releasing ACSL4. Mitochondria increases ROS levels via different cycles, including the Fenton reaction and TCA. Iron accumulation, the product of ferritinophagy or degradation of SLC40A1, provides an ingredient for the Fenton reaction. Ferritinophagy is also enhanced by autophagy receptors, NCO4, or SQSTM1. Lipid peroxidation results in ferroptosis and pore formation, which NUPR1 can inhibit. Abbreviations: SLC32A, Solute Carrier Family 32; ASLC7A11, Solute Carrier Family 7A11; AFT4, Adaptive Fourier Transform 4; GSH, glutathione; GSSG, oxidized glutathione; GPX4, glutathione peroxidase 4; HSP90, Heat Shock Protein 90; HSP5A, Heat Shock Protein 5A; ROS, Reactive Oxygen Species; NUPR1, Nuclear Protein 1; ACSL4, Acyl-CoA Synthetase Long-Chain Family Member 4; ACACA, Acetyl-CoA Carboxylase Alpha; FA, fatty acid; FASN, fatty acid synthase; PUFA, Polyunsaturated Fatty Acid; ALOX, Arachidonate Lipoxygenase; PLOOH, phospholipid hydroperoxide; NCO4, nuclear coactivator 4; SQSTM1, sequestosome 1. Created with BioRender.com. Accessed on 30 July 2023.

Figure 2

Necroptosis signaling pathways. Binding death receptor family (Fas receptor, TNFR1, and TRAIL-R) and other immunological receptors (TLRs and IFNR) to their ligands leads to the activation of initiator factors. Complex I members (TRADD, TRAF2/5, cIAP1/2, and RIPK1) are activated by TNFR-1 stimulation. This process inhibits the formation of complex II groups, including complex IIa (caspase-8, FADD, and RIPK1) and complex IIb (caspase-8, FADD, RIPK1, RIPK3, and MLKL). RIPK1 deubiquitylation leads to the formation of complex II groups, promoting downstream events. So cell fate depends on how RIPK1 changes, which can also be activated independently of complex I. Activating RIPK1 by Fas, TRAIL-R, INFR, and ZBP 1 stimulates complex IIa and IIb independently of complex I. Additionally, extrinsic factors like LPS stimulate TLR4, directly resulting in the activation of complex IIb. OXPHOS dysfunction or PARP1 overactivity by reducing ATP and increasing ROS stimulates complex IIb. Activation of RIPK3 by inactivated caspase-8 results in phosphorylation and oligomerization of MLKL, which translocates to the cell membrane, causing membrane rupture and release of DAMPs. Abbreviations: TNFR1, Tumor Necrosis Factor Receptor 1; TRAIL-R, TNF-Related Apoptosis-Inducing Ligand Receptor; TLRs, toll-like receptors; IFNR, interferon receptor; TRADD, TNFR1-Associated Death Domain; TRAF2/5, TNF Receptor-Associated Factor 2/5; cIAP1/2, Cellular Inhibitor of Apoptosis Protein 1/2; RIPK1, Receptor-Interacting Protein Kinase 1; MLKL, mixed lineage kinase domain-like; LPS, lipopolysaccharide; OXPHOS, oxidative phosphorylation; PARP1, Poly(ADP-ribose) Polymerase 1; ATP, Adenosine Triphosphate; ROS, Reactive Oxygen Species; ZBP1, Z-DNA Binding Protein 1. Created with BioRender.com. Accessed on 30 July 2023.

Figure 3

Pyroptosis signaling pathways. Activation of every member of the non-canonical caspase family (caspase-4/-5/-11) via bacterial LPS initiates the non-canonical pyroptosis signaling pathway. The canonical signaling pathway is triggered by the activation of NLRP3 via PAMPs or DAMPs or by directly activating caspase1 via the MST1 byproduct (ROS), the main functional component of the inflammasome group. GSDM, the main executor of pyroptosis, is cleaved both by a canonical and non-canonical pathway, leading to the activation of the N-terminal domain, which results in the formation of pores. The other products of the canonical pathway are activated IL-1β and IL-18, which are released from the cell with DAMPs via GSMD-induced pores. Abbreviations: LPS, lipopolysaccharide; PAMPs, pathogen-associated molecular patterns; DAMPs, damage-associated molecular patterns; NLRP3, NOD-like Receptor Family Pyrin Domain Containing 3; ROS, Reactive Oxygen Species; GSDM, gasdermin; IL-1β, Interleukin-1 Beta; IL-18, Interleukin-18; MST1, Mammalian Sterile 20-Like Kinase 1. Created with BioRender.com. Accessed on 30 July 2023.