Effect of regulatory cell death on the occurrence and development of head and neck squamous cell carcinoma

Abstract

Head and neck cancer is a malignant tumour with a high mortality rate characterized by late diagnosis, high recurrence and metastasis rates, and poor prognosis. Head and neck squamous cell carcinoma (HNSCC) is the most common type of head and neck cancer. Various factors are involved in the occurrence and development of HNSCC, including external inflammatory stimuli and oncogenic viral infections. In recent years, studies on the regulation of cell death have provided new insights into the biology and therapeutic response of HNSCC, such as apoptosis, necroptosis, pyroptosis, autophagy, ferroptosis, and recently the newly discovered cuproptosis. We explored how various cell deaths act as a unique defence mechanism against cancer emergence and how they can be exploited to inhibit tumorigenesis and progression, thus introducing regulatory cell death (RCD) as a novel strategy for tumour therapy. In contrast to accidental cell death, RCD is controlled by specific signal transduction pathways, including TP53 signalling, KRAS signalling, NOTCH signalling, hypoxia signalling, and metabolic reprogramming. In this review, we describe the molecular mechanisms of nonapoptotic RCD and its relationship to HNSCC and discuss the crosstalk between relevant signalling pathways in HNSCC cells. We also highlight novel approaches to tumour elimination through RCD.

Fig. 1

Core molecular mechanisms of apoptosis, necroptosis, pyroptosis, ferroptosis, autophagy and cuproptosis. A In the exogenous apoptosis pathway, TNF interacts with TNFR1, and TNFR1 begins to recruit downstream protein molecules to form complexes I and IIa, which promote the activation of caspase-8 and then activate caspase-3 and caspase-7. In the endogenous apoptotic pathway, activation of BH3-only proteins leads to Bax and BAK activity, triggering MOMP. Cyto C is released from mitochondria and forms a multiapoptotic complex with APAF1, which activates caspase-9 and then caspase-3 and caspase-7, leading to apoptosis. B TNF interacts with TNFR1; when caspase 8 is inhibited, activated RIPK1 promotes RIPK3 recruitment and MLKL phosphorylation, forms complex IIb, promotes inflammatory signal secretion, and promotes necroptosis. C PAMP and DAMP stimulate inflammasome activation, which leads to caspase-1 cleavage, and LPS can bind to caspase-4/5/11 to lyse GSDMD. Potassium efflux triggers the release of HMGB1 and K+. Caspase-3 can also be activated through the mitochondrial endogenous pathway and death receptor pathway to lyse GSDME and trigger pyroptosis. D Iron accumulation is achieved by increasing iron uptake by the TF-TFRC complex, limiting iron efflux by iron export transporters, and reducing iron storage by ferritosis. Cells obtain cysteine and exchange it for glutamate through the XC − antitransporter system. The ACSL4-LPCAT3-AlOXs pathway promotes iron death by activating lipid peroxidation to produce PLOOH from polyunsaturated fatty acids. E AMPK and mTORC1 act on mTOR, the ULK1 complex is phosphorylated, and the PI3K complex interacts with autophagosomes. Lc3 is modified to form LC3-II and ATG5-ATG12-ATG16L complexes to promote the formation and maturation of autophagic vesicles and binds to lysosomes under the action of LAMP, Rab7 and VAMP7. The recovered product is released into the cytosol for reuse. F Elesclomol binds extracellular copper (Cu2+) and transports it into the cell. FDX1 reduces Cu2 + to Cu + and promotes lipolylation (LA) and aggregation of DLAT involved in the mitochondrial TCA cycle. Copper importers (e.g., SLC31A1) and exporters (e.g., ATP7B) modulate copper sensitivity by affecting intracellular copper ion levels

Fig. 2

Modulation of cell death pathways in HNSCC. The tumour microenvironment of HNSCC is a complex ecosystem composed of cellular components (such as malignant cells, immune cells and stromal cells), extracellular matrix and interstitial fluid (such as blood vessels, cytokines, chemokines and growth factors). The interaction between cancer cells and invasive immune cells determines the progression and therapeutic effect of the tumour. ECM, extracellular matrix; NK, natural killer; TP53, tumour protein p53

Fig. 3

TP53 in HNSCC cell death. Tumour protein p53 (TP53) acts on mitochondria. MOMP inhibits BCL-2 and BCL-2L1, as antiapoptotic members, and activates BAX, BBC3 (also known as PUMA) and PMAIP1 (also known as NOXA), which are proapoptotic members of the Bcl2 family, thus triggering TP53-dependent apoptosis. P53 can also downregulate the mTOR signalling pathway to promote autophagy. TP53 induces iron death by inhibiting the expression of SLC7A11 or directly acting on diamine acetyltransferase SAT1 and mitochondrial glutaminase GLS2. TP53 inhibits iron death by inhibiting the activities of dipeptidyl peptidase 4 (DPP4) and NADPH oxidase 1 (NOX1) or inducing the expression of cyclin-dependent kinase inhibitor 1 A (CDKN1A). BAK1, BCL-2 homologous antagonist/killer 1; BBC3, BCL-2-binding component 3; CDKN1A, cyclin-dependent kinase inhibitor 1 A; CYCS, cytochrome C, somatic; GLS2, glutaminase 2; GPX4, glutathione peroxidase 4; GSH, glutathione; mTOR, mechanistic target of rapamycin kinase; PMAIP1, phorbol-12–myristate-13 acetate-induced protein 1; ROS, reactive oxygen species; SLC7A11, solute carrier family 7 member 11; SAT1, spermidine/spermine N1-acetyltransferase 1

Fig. 4

Induction of cell death by therapeutic regimens evokes antitumour immune responses. Therapeutic modalities, including apoptosis, necroptosis, pyroptosis, ferroptosis, autophagy, and cuproptosis, induce death in cancer cells. Apoptosis, necroptosis, pyroptosis, ferroptosis, autophagy and cuproptosis in cancer generate abundant neoantigens, which are processed by antigen-presenting cells to promote the formation of antigen-specific cytotoxic T lymphocytes (CTLs), thereby evoking antitumour immunity. Agents that target apoptosis, necroptosis, pyroptosis, ferroptosis, and autophagy are noted in the figure (apoptosis inhibitor: CmpdA, CREB5; necroptosis inducer: ASTX660, birinapant; pyroptosis inducer: 5-FU, T22-PE24H6, T22-Ditox-H6; ferroptosis inducer: RSL3, ML210, SAS; ferroptosis inhibitor: XCT; autophagy inhibitor: afatinib, CQ, 3-MA, bortezomib, trichostatin)