Exploring beyond Common Cell Death Pathways in Oral Cancer: A Systematic Review

Abstract

Oral squamous cell carcinoma (OSCC) is the most common and lethal type of head and neck cancer in the world. Variable response and acquisition of resistance to traditional therapies show that it is essential to develop novel strategies that can provide better outcomes for the patient. Understanding of cellular and molecular mechanisms of cell death control has increased rapidly in recent years. Activation of cell death pathways, such as the emerging forms of non-apoptotic programmed cell death, including ferroptosis, pyroptosis, necroptosis, NETosis, parthanatos, mitoptosis and paraptosis, may represent clinically relevant novel therapeutic opportunities. This systematic review summarizes the recently described forms of cell death in OSCC, highlighting their potential for informing diagnosis, prognosis and treatment. Original studies that explored any of the selected cell deaths in OSCC were included. Electronic search, study selection, data collection and risk of bias assessment tools were realized. The literature search was carried out in four databases, and the extracted data from 79 articles were categorized and grouped by type of cell death. Ferroptosis, pyroptosis, and necroptosis represented the main forms of cell death in the selected studies, with links to cancer immunity and inflammatory responses, progression and prognosis of OSCC. Harnessing the potential of these pathways may be useful in patient-specific prognosis and individualized therapy. We provide perspectives on how these different cell death types can be integrated to develop decision tools for diagnosis, prognosis, and treatment of OSCC.

Keywords: emerging types of cell death; ferroptosis; necroptosis; oral cancer; pyroptosis; systematic review; tumor microenvironment.

Figure 1

Flow diagram of literature search and selection criteria adapted from Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).

Figure 2

Ferroptosis manifests through two primary pathways. In the first pathway, transferrin (TRF1), a crucial player in iron homeostasis, binds to Fe³⁺, forming a complex, which then binds to the transferrin receptor. Endocytosis of this complex occurs, leading to the formation of the endosome. Within the endosome, there will be acidification of the environment, causing the dissociation of the complex and the reduction of Fe³⁺ to Fe²⁺. This Fe²⁺ is released through the endosomal membrane. However, surplus free iron ions form a labile iron pool (LIP), which partakes in Fenton’s reactions, causing the generation of the reactive oxygen species (ROS) free radical hydroxyl. This cascade of events culminates in the initiation of lipoperoxidation, a critical step in the ferroptotic process. In the second pathway, System Xc-, a cystine/glutamate antiporter, imports extracellular cystine. Intracellularly, cystine undergoes conversion into glutathione (GSH), a vital antioxidant. The availability of GSH is integral to the function of glutathione peroxidase 4 (GPX4), which tackles intracellular lipid peroxides, preventing ferroptosis. However, the inhibition of GPX4 leads to a disruption in this protective mechanism, resulting in an augmented presence of ROS and ultimately contributing to the progression of ferroptosis. [Image was created using Biorender.com (accessed on 16 November 2023)].

Figure 3

Pathways related to activation of pyroptosis. In the canonical signaling pathway, intracellular sensors Nod-like receptor family, pyrin domain containing 1 (NLRP1), 3 (NLRP3), 4 (NLRC4), absent in melanoma 2 (AIM2) and other inflammasome sensors are responsible for detecting microbial signals. Upon detection, they initiate a response by recruiting the adaptor protein ASC (apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain), which subsequently recruits pro-caspase-1. Once activated, caspase-1 cleaves Gasdermin D (GSDMD), generating GSDMD-NT fragments. These GSDMD-NT fragments create pores in the plasma membrane that are associated with phosphoinositides. Simultaneously, caspase-1 itself undergoes cleavage, giving rise to caspase-1 P10/P20 and P33/P10 tetramers. These tetramers play a crucial role in the maturation of pro-interleukin-18 (IL-18) and pro-interleukin-1β (IL-1β) into their active forms, IL-18 and IL-1β. These mature cytokines are subsequently released into the extracellular matrix, leading to the initiation of inflammatory responses. In the noncanonical pathway, the presence of lipopolysaccharides (LPS) from Gram-negative bacteria triggers the activation of caspase-4 and caspase-5 (in humans) or caspase-11 (in mice). These caspases, in turn, cleave GSDMD, forming pores in the plasma membrane. These GSDMD pores permit the release of potassium ions, which further activate the NLRP3 inflammasome and contribute to the maturation of IL-1β and IL-18. Additionally, GSDMD pores release mature cytokines, ultimately leading to pyroptosis. [Image was created using Biorender.com (accessed on 13 December 2023)].

Figure 4

Necroptosis signaling pathway. The binding of tumor necrosis factor (TNF) induces the formation of the membrane-associated complex I, composed of TNF receptor-associated death domain (TRADD), TNF receptor-associated factor 2 (TRAF2), cellular inhibitor of apoptosis protein 1 and 2 (cIAP1/2), receptor-interacting serine/threonine kinase 1 (RIPK1), and LUBAC, an E3 ubiquitin ligase. cIAP1/2 and LUBAC induce the polyubiquitination of RIPK1, recruiting the IκB kinase (IkappaB kinase) complex (IKKa, IKKB, and NEMO) and TGF-β-activated kinase 1 (TAK1) complex (TAK1, TAB1, and TAB2). These two complexes can eventually lead to the activation of the NF-κB pathway and cell survival. A20CYLD promotes the deubiquitination of RIPK1, inducing the dissociation of TRADD and RIPK1 from TNFR1 and leading to the formation of complex IIa or complex IIb. Complex IIa, consisting of TRADD and Fas-associated protein with death domain (FADD), activates caspase-8 and induces apoptosis through cleavage. Inhibition of RIPK1 ubiquitination results in the induction of complex IIb, composed of RIPK1, FADD and caspase-8. When caspase-8 is inhibited (in either complex IIa or IIb), RIPK1 and RIPK3 form necrosome complexes, activating MLKL through a phosphorylation cascade. Phosphorylated MLKL undergoes oligomerization and migrates to the membrane, which induces necroptosis by membrane rupture or regulating ion flow. [Image was created using Biorender.com (accessed on 16 November 2023)].