Targeting regulated cell death pathways in cancers for effective treatment: a comprehensive review

Abstract

Cancer is a complex disease characterized by specific "mission-critical" events that drive the uncontrolled growth and spread of tumor cells and their offspring. These events are essential for the advancement of the disease. One of the main contributors to these events is dysregulation of cell death pathways-such as apoptosis, necroptosis, ferroptosis, autophagy, pyroptosis, cuproptosis, parthanatos and-allows cancer cells to avoid programmed cell death and continue proliferating unabated. The different cell death pathways in cancers provide useful targets for cancer treatment. This review examines recent progresses in the preclinical and clinical development of targeting dysregulated cell death pathways for cancer treatment. To develop effective cancer therapies, it is essential to identify and target these mission-critical events that prevent tumor cells from timely death. By precisely targeting these crucial events, researchers can develop therapies with maximum impact and minimal side effects. A comprehensive understanding of the molecular and cellular mechanisms underlying these regulated cell death pathways will further the development of highly effective and personalized cancer treatments.

Keywords: apoptosis; autophagy; cancer therapy; cuproptosis; ferroptosis; necroptosis; pyroptosis; regulated cell death pathway.

FIGURE 1

Regulated cell death pathways in cancer and their associated genes. For each RCD pathway, a set of key regulators are listed and the change of expression levels are indicated. Figure created using Biorender.

FIGURE 2

An overview of regulated cell death processes. A summary of the RCD pathways involved in cancer pathogenesis. Intrinsic apoptosis: Following an inherent fatal signal, BH3-only proteins activate BAX and BAK either directly or indirectly by binding to and blocking BCL-2 proteins. The mitochondrial outer membrane is then permeabilized (MOMP), releasing cytochrome C (Cyt C) and SMAC, the latter of which can suppress apoptosis. The apoptosome is subsequently produced, which activates caspase-9, followed by caspases 3 and 7, and initiates apoptosis. Extrinsic apoptosis: When death receptors (TNFR1, FAS, or TRAIL-R) receive an extrinsic fatal signal, they join with pro-caspase-8 and -10 to create complex I. Complex IIa is then generated, resulting in caspase-8 and -10 activation. Apoptosis is then initiated either directly by cleaving caspases-3 and -7, or indirectly by cleaving BID into tBID and activating BAX and BAK. Granzyme pathway: Cytotoxic T-cells are the main controllers for the granzyme pathway, which results in caspase-10 activation that in turn activates caspase-3. Granzyme B can activate caspases in the targeted cell. Necroptosis occurs when an extrinsic fatal signal is received but caspase-8 is not activated. Complex IIb (also known as the necrosome) is generated. This causes RIPK 1 and 3 to phosphorylate and activate mixed lineage kinase domain-like pseudokinase (MLKL). MLKL then forms a complex, causing the release of cytokines, chemokines, and damage-associated molecular patterns (DAMPS). Finally, this causes inflammation and necroptosis of the cell. Pyroptosis occurs when toll-like receptors (e.g., TLR4) detect an external fatal signal. Nuclear factor kappa B (NF-KB) signaling is initiated. This causes inflammasome development and subsequent caspase-1 activation. Then, pro-IL-1b is converted to active IL-1b, and gasdermin D (GSDMD) is broken down into N-GSDMD fragments resulting in inflammation and pyroptosis of the cell. Parthanatos occurs when an inherent fatal signal arises (for example, high reactive oxygen species accumulation), poly [ADP-ribose] polymerase 1 (PARP-1) is activated. Overactivation of PARP-1 can result in the accumulation of PAR polymer and the translocation of apoptosis inhibitory factor (AIF) from the mitochondria. AIF forms a compound with macrophage migration inhibitory factor (MIF) and re-enters the nucleus. Ultimately, this leads to cell parthanatos and DNA fragmentation. Autophagic Cell Death: Beclin-1 generally forms a complex with Bcl-2 proteins. After they have been phosphorylated and inactivated, free Beclin-1 can start autophagy. Ferroptosis occurs exclusively when there is an imbalance in the regulatory system, leading to the accumulation of lipid peroxide to a lethal threshold. Transferrin (TF) binds to extracellular Fe3+ and facilitates its transport into cells via transferrin receptor 1 (TfR1), where it is then converted to Fe2+. Later, intracellular divalent metal transporter 1 (DMT1) and zinc transporter 8/14 (ZIP8/14) store the Fe2+ in the intracellular labile iron pool (LIP). Fe2+ transfers electrons through the Fenton reaction with peroxide, resulting in the production of oxidizing free radicals. Following an excessive accumulation of iron within cells, numerous free radicals interact with polyunsaturated fatty acids (PUFA) found in the phospholipids of cell membranes resulting in the formation of lipid peroxides, which ultimately lead to cell death. The intracellular antioxidant stress system depends on GPX4 to eliminate surplus lipid peroxides. The Cystine/glutamate antiport (system xc−) facilitates the movement of glutamate from within cells to the outside, while simultaneously transporting cystine from the outside into cells. Cuproptosis: FDX1 plays a crucial role as a copper ion carrier in the induction of cell death and is involved in the regulation of protein lipoylation. Elevated copper levels foster the accumulation and functional impairment of lipoylated proteins, leading to instability of iron–sulfur cluster proteins, protein toxicity stress, and ultimately cell death. In addition, excessive copper binds to lipoylated DLAT, triggering abnormal oligomerization of DLAT and the formation of DLAT foci. This process contributes to cellular protein toxicity stress, further exacerbating cell death. Figure created using Biorender.