To the Editor: Tumors are one of the main causes of death worldwide. Pyroptosis is a newly discovered form of cell death, causing cell swelling and rapid lysis, which releases pro-inflammatory mediators and enhances the inflammatory response. Inflammation increases the immune response to tumors and inhibits their progression. The ultimate goal of cancer therapeutics is to maximize the destruction of tumor cells while minimizing the damage to normal tissues. Targeting pyroptosis of tumor cells could overcome the apoptotic resistance and trigger antitumor immunity, thus being a good treatment for tumors.
Pyroptosis, a new form of cell death, plays an important role in the development of tumors and is mediated by gasdermin (GSDM) family proteins. Caspase-8 functions as the initiator caspase that activates apoptosis and participates in the cleavage of gasdermin family proteins to induce pyroptosis, which improves the tumor microenvironment and enhances antitumor immunity. Gasdermins, a protein superfamily that consists of GSDMA, GSDMB, GSDMC, GSDMD, GSDME, and DFNB59 in humans, might play significant roles in inflammatory diseases. The granzyme-directed cleavage of GSDMB and GSDME plays an antitumor role in cancer cells. Unexpectedly, GSDME is highly expressed in normal cells but is scarcely expressed in tumor cells. The administration of chemotherapeutic drugs leads to normal pyroptosis in tumor cells. As a consequence, specifically inducing tumor cell pyroptosis and avoiding damage to normal cells and tissue has become a key issue.
Alpha-ketoglutarate (α-KG) is a vital metabolite in the tricarboxylic acid cycle that plays an important regulatory role in physiological processes such as lipid synthesis, oxidative stress, and cell death. Moreover, α-KG functions as an antitumor metabolite and suppresses breast cancer oncogenesis by switching metabolism from glycolysis to oxidative phosphorylation. Despite α-KG could have the potential effect of antitumor, the role of α-KG in pyroptosis is not reported. Using mouse models of tumors, Zhang et al recently provided a novel mechanism by which the metabolite α-KG regulates the death receptor 6 (DR6)/caspase-8/gasdermin C (GSDMC) pathway, which inhibits tumor growth and metastasis. α-KG activates caspase-8 to cleave GSDMC, leading to tumor cell pyroptosis. DM-αKG, a cell-permeable derivative of α-KG, elevates reactive oxygen species (ROS) levels and then activates signaling in response to the plasma membrane-localized death receptor 6 (DR6). ROS-activated oxidation of DR6 promotes endocytosis and then forms DR6 receptosomes. Furthermore, internalized DR6 with the help of the adapter Fas-associated protein with death domain (FADD) recruits pro-caspase-8 and GSDMC into DR6 receptosomes, providing a platform for the cleavage of caspase-8-activated GSDMC. Interestingly, in an acidic environment, α-KG is reduced by malate dehydrogenases 1 (MDH1) and converted to L-2-hydroxyglutarate (L-2HG), which further increases ROS levels, making tumor cells more sensitive to α-KG-induced pyroptosis. Together, their research reveals a previously unappreciated pyroptotic pathway linking metabolites from ROS-initiated DR6 endocytosis to caspase-8-mediated cleavage of GSDMC for potential clinical application in the inhibition of tumor growth and metastasis [Figure 1].
α-KG activates caspase-8 to cleave GSDMC, leading to tumor cell pyroptosis. DM-αKG, a cell-permeable derivative of α-KG, elevates ROS levels and then activates signaling in response to the plasma membrane-localized DR6. ROS-activated oxidation of DR6 promotes endocytosis and then forms DR6 receptosomes. Furthermore, internalized DR6 with the help of the adapter FADD recruits pro-caspase-8 and GSDMC into DR6 receptosomes, providing a platform for the cleavage of caspase-8-activated GSDMC. Interestingly, in an acidic environment, α-KG is reduced by malate dehydrogenase 1(MDH1) and converted to L-2HG, which further increases ROS levels, making tumor cells more sensitive to α-KG-induced pyroptosis.
GSDMC functions as an oncogene and is highly expressed in cancers. Silencing GSDMC leads to a significant reduction in the proliferation and tumorigenesis of cancer cells. Caspase-8 is a molecular switch for apoptosis, necroptosis, and pyroptosis that may determine different types of cell death. DR6 is an upstream activator of caspase-8 and is activated by ROS induced by α-KG through oxidation, thus inducing pyroptosis. Studies have shown that GSDMC controls tricarboxylic acid (TNF)-α upon caspase-8 activation, liberating the N-terminal domain to trigger pyroptosis in tumor cells. During this process, specific recruitment of GSDMC to DR6 receptosomes via their interaction enables direct GSDMC cleavage by active caspase-8, leading to the initiation of pyroptosis but not apoptosis. Therefore, the cleavage of GSDMC may be a key target for oncotherapy and deserves further study.
L-2-hydroxyglurate (L-2HG) can inhibit leukemia and glioma cell proliferation and strengthen antitumor immunity. L-2HG increases ROS levels, maintains redox homeostasis, and plays a key role in α-KG-induced pyroptosis; thus, L-2HG has therapeutic potential against tumors by pyroptosis induction. However, accumulated 2HG in plasma causes progressive damage to the brain, and L-2HG for tumor therapy may lead to severe side effects. α-KG is metabolized into L-2HG by the metabolic enzyme MDH1 in an acidic environment, which sensitizes originally resistant cells to α-KG-induced pyroptosis. α-KG can effectively inhibit tumor growth and metastasis through pyroptosis induction without side effects, thus providing an alternative treatment approach. Currently, Zhang et al reported that α-KG-induced and GSDMC lysis-dependent pyroptosis could inhibit tumor growth and metastasis. In the future, it may be an exciting area to illuminate that the metabolite α-KG could have potential use as a therapeutic strategy for tumors without substantially compromising normal cells.
To sum up, Zhang et al revealed a hitherto unexplored mechanism by which the metabolite α-KG regulates the DR6/caspase-8/GSDMC pathway, including inhibiting tumor growth and metastasis. The metabolite α-KG is an appealing safe target for antitumor therapies that aim at increasing tumor cell pyroptosis. The development of new pyroptosis targeting α-KG could recruit and activate Caspase-8 to split GSDMC, thus providing a new therapeutic strategy for tumors.
This work was supported by grants from the National Natural Science Foundation of China (No. 81803535) and the Natural Science Foundation of Hunan Province (No. 2018JJ6070).
Conflicts of interest
1. Zhivaki D, Kagan JC. NLRP3 inflammasomes that induce antitumor immunity. Trends Immunol 2021;42:575–589. doi: 10.1016/j.it.2021.05.001.
2. Tan YX, Chen QZ, Li XL, Zeng ZY, Xiong W, Li GY, et al. Pyroptosis: a new paradigm of cell death for fighting against cancer. J Exp Clin Cancer Res 2021;40:153. doi: 10.1186/s13046-021-01959-x.
3. Jiang M, Qi L, Li L, Wu Y, Song D, Li Y. Caspase-8: a key protein of cross-talk signal way in “PANoptosis” in cancer. Int J Cancer 2021;149:1408–1420. doi: 10.1002/ijc.33698.
4. Zhang JY, Zhou B, Sun RY, Ai YL, Cheng K, Li FN, et al. The metabolite alpha-KG induces GSDMC-dependent pyroptosis through death receptor 6-activated caspase-8. Cell Res 2021;31:980–997. doi: 10.1038/s41422-021-00506-9.
5. Chen X, Zeh HJ, Kang R, Kroemer G, Tang DL. Cell death in pancreatic cancer: from pathogenesis to therapy. Nat Rev Gastroenterol Hepatol 2021;18:804–823. doi: 10.1038/s41575-021-00486-6.
6. Hou J, Zhao R, Xia W, Chang CW, You Y, Hsu JM, et al. PD-L1-mediated gasdermin C expression switches apoptosis to pyroptosis in cancer cells and facilitates tumour necrosis. Nat Cell Biol 2020;22:1264–1275.