Peptide analogues PKHB1 and 4N1K induce cell death through CD47‐independent mechanisms

Leclair, Pascal; Kim, Min Jung; Lim, C. J.

doi:10.1111/cas.14310

Cited by 7 publications

(8 citation statements)

References 10 publications

(14 reference statements)

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“…4N1K, a peptide corresponding to the CD47 binding region of TSP on IL-12 and TNF-α production, was reported to mediate significant biological effects that were CD47‐independent ( 19 – 21 ). PKHB1, the first‐described serum‐stable soluble CD47‐agonist peptide, directly induced T‐leukemic cell death by engaging the CD47 receptor ( 20 ).…”

Section: Ligands Of Cd47mentioning

confidence: 99%

CD47 as a promising therapeutic target in oncology

Zhao

Song

et al. 2022

Front. Immunol.

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CD47 is ubiquitously expressed on the surface of cells and plays a critical role in self-recognition. By interacting with SIRPα, TSP-1 and integrins, CD47 modulates cellular phagocytosis by macrophages, determines life span of individual erythrocytes, regulates activation of immune cells, and manipulates synaptic pruning during neuronal development. As such, CD47 has recently be regarded as one of novel innate checkpoint receptor targets for cancer immunotherapy. In this review, we will discuss increasing awareness about the diverse functions of CD47 and its role in immune system homeostasis. Then, we will discuss its potential therapeutic roles against cancer and outlines, the possible future research directions of CD47- based therapeutics against cancer.

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Section: Ligands Of Cd47mentioning

confidence: 99%

CD47 as a promising therapeutic target in oncology

Zhao

Song

et al. 2022

Front. Immunol.

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“…As such, stimulation of phagocytosis involves the delicate balance between CD47 down-regulation and calreticulin exposure on the cell surface. Using the TSP- However, it remains unclear if PKHB1 stimulation of immunogenic cell death is mediated via ligation of CD47, since both PKHB1 and 4N1K can effectively induce cell death in CD47-deficient leukemic cells (Leclair et al 2020).…”

Section: Cell Death Induced By Cd47-ligationmentioning

confidence: 99%

“…Specifically, a VVM motif at TSP’s C-terminus was found to mediate this interaction, from which the often-used 4N1K, 7N3, and more recently, PKHB1, peptides were subsequently derived and used as proxies for TSP activity (Gao and Frazier 1994 ; Martinez-Torres et al 2015 ). However, it must be noted that these peptides have been conclusively shown to exert a number of biological phenomena independent of their ligand interaction with CD47 (Tulasne et al 2001 ; Barazi et al 2002 ; Karki and Nichols 2014 ; Leclair and Lim 2014 ; Leclair et al 2020 ). Therefore, the usage of 4N1K-like peptides in experiments to study CD47 signaling should be carefully considered and critically evaluated.…”

Section: Cd47 Ligandsmentioning

confidence: 99%

“…Using the TSP-derived peptide, PKHB1, Martinez-Torres et al have shown that PKHB1-mediated cell death was potentially immunogenic by inducing cell surface presentation of damage-associated molecular pattern (DAMP) molecules including calreticulin (Martinez-Torres et al 2015 ; Martinez-Torres et al 2019 ; Uscanga-Palomeque et al 2019 ). However, it remains unclear if PKHB1 stimulation of immunogenic cell death is mediated via ligation of CD47, since both PKHB1 and 4N1K can effectively induce cell death in CD47-deficient leukemic cells (Leclair et al 2020 ).…”

Section: Cell Death Induced By Cd47-ligationmentioning

confidence: 99%

“…Indeed, calcium overload was proposed to mediate the effects of PKHB1 since BAPTA-AM – a cytoplasmic Ca 2+ chelator – and an inhibitor of the mitochondrial Ca 2+ uniporter, both abrogated the observed mitochondrial dysfunctions and cell death following PKHB1 treatment. However, these effects may not be CD47-mediated, as PKHB1 is known to induce activity in a CD47-independent manner (Leclair et al 2020 ). Using the CC2C6 antibody to induce CD47-dependent cell death, we observed significant increases in cytoplasmic Ca 2+ , however CC2C6-induced cell death was not attenuated upon chelation of calcium (Leclair et al 2018 ).…”

Section: Miscellaneous Phenotypes That Accompany Cd47-mediated Cell Dmentioning

confidence: 99%

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CD47 (Cluster of differentiation 47): an anti-phagocytic receptor with a multitude of signaling functions

Leclair

Lim

2020

Animal Cells and Systems

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CD47 is a tumor-associated antigen best known for its ability to bind counter-receptors on the surface of professional phagocytes as an immune-evasion strategy. Recently, CD47 has been shown to play a role as a signaling receptor, involving a number of cell physiological processes. This review provides a comprehensive survey of the signaling pathways triggered by CD47 ligand-mediated cell death in tumor cells. Such an understanding should lead to improvement of CD47-targeted anti-tumor therapeutics able to both neutralize the anti-phagocytic role and trigger autonomous tumor cell death.

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Thrombospondin‐1 mimic peptide PKHB1 induced endoplasmic reticulum stress‐mediated but CD47‐independent apoptosis in non‐small cell lung cancer

Yao

Zhao

et al. 2023

Drug Development Research

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Non-small cell lung cancer (NSCLC) is one of the most common malignancies with high morbidity and mortality. PKHB1, a serum-stable Thrombospondin-1 (TSP-1) mimic peptide, has shown some effective ability in triggering cell death against several cancers. Here, we aimed to study the potential biological function of PKHB1 and its molecular mechanism in NSCLC. Our results revealed that PKHB1 significantly suppressed NSCLC cell proliferation, cell migration, and induced apoptosis in a dose-dependent manner. Additionally, we found that PKHB1 treatment resulted in mitochondrial transmembrane potential depolarization, Ca 2+ overloading as well as the upregulation of proapoptotic proteins. Mechanistically, PKHB1 induced NSCLC cells apoptosis in a CD47-independent manner. Further study revealed that PKHB1 provoked endoplasmic reticulum (ER) stress principally through the activation of CHOP and JNK signaling, which could be alleviated in the presence of 4-PBA, an ER stress inhibitor. Furthermore, xenograft tumor models showed that PKHB1 treatment could notably inhibit NSCLC tumor growth in vivo. In conclusion, these findings suggested that PKHB1 exerted antitumor efficacy in NSCLC via triggering ER stress-mediated but CD47-independent apoptosis, potentially functioned as a promising peptide-based therapeutic agent for NSCLC.

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Peptide analogues PKHB1 and 4N1K induce cell death through CD47‐independent mechanisms

Cited by 7 publications

References 10 publications

CD47 as a promising therapeutic target in oncology

CD47 as a promising therapeutic target in oncology

CD47 (Cluster of differentiation 47): an anti-phagocytic receptor with a multitude of signaling functions

Thrombospondin‐1 mimic peptide PKHB1 induced endoplasmic reticulum stress‐mediated but CD47‐independent apoptosis in non‐small cell lung cancer

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