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Review
. 2022 Aug 13;7(1):286.
doi: 10.1038/s41392-022-01110-y.

Regulated cell death (RCD) in cancer: key pathways and targeted therapies

Fu Peng #  1 , Minru Liao #  1 , Rui Qin #  2 , Shiou Zhu  1   3 , Cheng Peng  2 , Leilei Fu  4 , Yi Chen  5 , Bo Han  6
Affiliations
Review

Regulated cell death (RCD) in cancer: key pathways and targeted therapies

Fu Peng et al. Signal Transduct Target Ther. .

Abstract

Regulated cell death (RCD), also well-known as programmed cell death (PCD), refers to the form of cell death that can be regulated by a variety of biomacromolecules, which is distinctive from accidental cell death (ACD). Accumulating evidence has revealed that RCD subroutines are the key features of tumorigenesis, which may ultimately lead to the establishment of different potential therapeutic strategies. Hitherto, targeting the subroutines of RCD with pharmacological small-molecule compounds has been emerging as a promising therapeutic avenue, which has rapidly progressed in many types of human cancers. Thus, in this review, we focus on summarizing not only the key apoptotic and autophagy-dependent cell death signaling pathways, but the crucial pathways of other RCD subroutines, including necroptosis, pyroptosis, ferroptosis, parthanatos, entosis, NETosis and lysosome-dependent cell death (LCD) in cancer. Moreover, we further discuss the current situation of several small-molecule compounds targeting the different RCD subroutines to improve cancer treatment, such as single-target, dual or multiple-target small-molecule compounds, drug combinations, and some new emerging therapeutic strategies that would together shed new light on future directions to attack cancer cell vulnerabilities with small-molecule drugs targeting RCD for therapeutic purposes.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Crucial signaling pathways of RCD subroutines in cancer
Fig. 2
Fig. 2
Small-molecule compounds targeting apoptosis-related pathways in cancer. There are two core apoptosis pathways, intrinsic and extrinsic. The extrinsic pathway is initiated by multiple death receptors, such as TNFR1, Fas, and DR4/5. The intrinsic pathway is mediated by Bcl-2 family proteins. Activation of either pathway ultimately triggers a cascade of caspases, thus inducing caspase-dependent nucleosome fragmentation leading to cell death. In addition, NF-κB, JAK-STAT3, and MAPKs signaling pathways play an essential role in regulating cell apoptosis
Fig. 3
Fig. 3
Small-molecule compounds targeting autophagy-dependent cell death pathways in cancer. Autophagy is a complex process regulated by multiple signaling pathways. ULK1 complex is essential during the early-stage initiation of autophagy. ULK1 could be phosphorylated by mTOR or AMPK, which promotes the binding of Beclin-1 to vacuolar protein sorting 34 (VPS34) and ultimately participates in the regulation of autophagy. Autophagy-related signaling pathways, including the Ras/Raf/MEK/ERK pathway, PI3KC1/Akt/mTORC1 pathway, and NF-κB pathway, are significant to autophagy signal transduction and mediate the occurrence of autophagic cell death. p53 is a tumor suppressor protein. Nuclear p53 stimulates autophagy through translocation activation, and cytoplasmic p53 represses autophagy. FoxO regulates autophagy by transcriptional dependent mechanism. p62 is also a key regulator of autophagy that can directly bind to LC3 to promote the formation of autophagosomes
Fig. 4
Fig. 4
Small-molecule compounds targeting necroptosis pathways in cancer. There are three main pathways to fight tumor by targeting necroptosis. In TNF-α After binding with TNFR1 on the plasma membrane, the downstream protein molecules TRADD, TRAF, cIAPs, LUBA and RIPK1 are recruited to form complex I and activate NF-κB to promote the survival of tumor cells. Then RIPK1 promotes the recruitment of pro-caspase-8 to produce activated Caspase-8 and form complex IIa. If caspase-8 is inhibited or there is no expression of caspase-8, RIP3 is recruited to form rip1-rip3 necrosome, causing ripk3 phosphorylation, MLKL is recruited to form complex IIb and induce necroptosis. In addition, TLR ligand can also mediate RIPK3-MLKL dependent necrosis through TICAM1. ZBP1 acts upstream of RIPK3 and interacts with RIPK3 through its RHIM domain to mediate necroptosis in response to viral infection
Fig. 5
Fig. 5
Small-molecule compounds targeting pyroptosis pathways in cancer. There are two main pathways and two other pathways that exert antitumor activity by targeting pyroptosis. Pyroptosis pathway can be divided into classical pyroptosis pathway and non-classical pyroptosis pathway. The activation of classical pyroptosis pathway is initiated by PAMPs or damps. After NLRs or ALRs recognize specific stimuli, they start to assemble to form inflammatory bodies and process to form activated caspase-1. Caspase-1 cuts GSDMD, and the N-terminal of GSDMD is located and aggregated on the cell membrane to form pores. In addition, caspase-1 cleaves pro-IL-1β and pro-IL-18 to form mature IL-1β and IL-18, and the intracellular contents are secreted outside the membrane through the membrane pore. The nonclassical focal death pathway depends on the activation of caspase-4/Caspase-5/caspase-11. After stimulated by LPS in the cytoplasm, caspase-4/Caspase-5/caspase11 can directly bind to the conserved structure lipid A of LPS, cause oligomerization and activation, further cut GSDMD, cause the N-terminal of GSDMD to disintegrate and locate in the cell membrane to form membrane pores. In caspase-3-dependent cell death, GSDME is the reaction substrate of Caspase-3. GSDME can be cleaved by activated caspase-3 to generate its N-terminal fragment, which performs pyroptosis by penetrating the plasma membrane. Granzyme B can also participate in NK cell induced pyroptosis by cleaving GSDME. In addition, TNF-γ acts on TNFR, activates the N-terminal cleavage of GSDMC mediated by caspase-8, locates in the cell membrane, forms membrane pores, and finally induces pyroptosis. IFN-γ by acting on ifngr, causes the N-terminal of GSDMB to cleave and locate to the cell membrane to form membrane pores and induce pyroptosis. Granzyme A can also induce pyroptosis by cleaving GSDMB
Fig. 6
Fig. 6
Small-molecule compounds targeting ferroptosis pathways in cancer. There are two main pathways to exert antitumor activity by targeting ferroptosis. The intracellular antioxidant stress system mainly relies on GPX4 to remove excess lipid peroxide. GPX4 of the antioxidant system will reduce the lipid peroxide PL-OOH to the corresponding lipid alcohol PL-OH, so as to reduce the burden of lipid peroxidation and protect the cell membrane from damage. Cystine enters the cytoplasm through SLC7A11, transforms into cystine, and enters the GSH biosynthesis pathway. GSH is involved in the hydrolysis of PL-OOH by GPX4. The inhibition of GSH synthesis or the inactivation of GPX4 can make the excess PL-OOH in cells unable to be cleared, resulting in cell oxidative damage and the occurrence of ferroptosis. It is worth noting that in this process, BAP1, ATF3, Beclin1 and p53 will inhibit the function of SLC7A11. When intracellular iron is overloaded, a large number of free radicals can react with PUFA of cell membrane phospholipids under the catalysis of ester oxygenase and iron, and produce a large number of PL-OOH through the promotion of POR, a positive regulatory protein of iron death phospholipid peroxidation in tumor cells, resulting in ferroptosis. In addition to the direct pathway of PUFA mediated PL-OOH production, PUFA can also be incorporated into phospholipid membrane through ACSL4, esterified into PUFA COA, esterified into PL through LPCAT3, and then oxidized into toxic PL-OOH by lipoxygenases (LOXs). In addition, the extracellular Fe3+ is combined with transferrin, transported into the cell through TFR1 and reduced to Fe2+, and then stored in the intracellular LIP with the help of intracellular NRF2. Fe2+ can transfer electrons to produce free radicals or ROS with oxidation ability through Fenton reaction with peroxide, so as to promote the oxidation process of LOXs
Fig. 7
Fig. 7
Small-molecule compounds targeting other pathways of RCD in cancer. Other main subroutines of RCD include parthanatos, entosis, NETosis and LCD. A When DNA is lost, PARP-1 is abnormally activated to produce a large amount of par. When the mitochondrial membrane is depolarized, the levels of ATP and NADPH decrease. AIF enters the nucleus from mitochondria, chromatin condenses and produces a large number of DNA fragments ranging from 15 KB to 50 KB, which induces the occurrence of parthanatos and promotes or inhibits tumorigenesis. B Entosis is an RCD form of "cannibalism" of cells. One cell engulfs and kills another cell, which is characterized by CIC structure. Cell adhesion and cytoskeleton rearrangement pathways (such as myosin, RhoA and ROCK) and other signaling molecules and regulatory factors (such as CDC42) play an important role in regulating the induction of entosis. It is worth noting that entosis can promote tumorigenesis through cell division and escape, or inhibit tumorigenesis through LCD and apoptosis. C The process of neutrophils secreting nets is called NETosis, which can promote tumor recurrence and metastasis. Overexpression of G-CSF and IL-8 in tumors can increase the number of neutrophils in blood, produce ROS and cause the formation of nets. In addition, NADPH oxidase can also directly produce ROS and promote the formation of nets. D When cells are exposed to lysosomal detergent, dipeptide methyl ester, lipid metabolites and ROS, lysosomes rupture and LCD is mediated by hydrolase or iron released by LMP, which inhibits the occurrence and development of tumors
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