The anticancer peptide RT53 induces immunogenic cell death

Pasquereau-Kotula, Ewa; Habault, Justine; Kroemer, Guido; Poyet, Jean-Luc

doi:10.1371/journal.pone.0201220

Cited by 50 publications

(44 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similar results were obtained with inhibition of caspase-1, caspase-3/7 and caspase-8 (Figure S3B). These results are in agreement with caspase-independent mechanism of cytotoxicity induced by RT53 in cancer cells (24).…”

Section: Resultssupporting

confidence: 90%

“…Although the mechanisms associated with its anti-apoptotic activity have not been clearly elucidated, AAC-11 contains several protein interaction domains, including a leucine zipper (LZ) domain (19), and has been proposed to repress apoptotic effectors such as E2F1 (20), Acinus (21) and caspase-2 (22). Synthetic peptides based on the LZ domain sequence of AAC-11 were previously shown to be cytotoxic to cancer cells both in vitro and in a in vivo mouse model of melanoma (23, 24) or acute leukemia (25).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Anti-apoptotic clone 11 derived peptides induce in vitro death of CD4+ T cells susceptible to HIV-1 infection

Mikhailova

Valle-Casuso

David

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

ABSTRACTHIV-1 successfully establishes long-term infection in its target cells despite viral cytotoxic effects. We have recently shown that cell metabolism is an important factor driving CD4+ T-cell susceptibility to HIV-1 and the survival of infected cells. We show here that expression of anti-apoptotic clone 11 (AAC-11), an anti-apoptotic factor upregulated in many cancers, increased with progressive CD4+ T cell memory differentiation in association with the expression of cell cycle, activation and metabolism genes and correlated with susceptibility to HIV-1 infection. Synthetic peptides based on the LZ domain sequence of AAC-11, responsible for its interaction with molecular partners, were previously shown to be cytotoxic to cancer cells. Here we observed that these peptides also blocked HIV-1 infection by inducing cell death of HIV-1 susceptible primary CD4+ T-cells across all T-cell subsets. The peptides targeted metabolically active cells and had the greatest effect on effector and transitional CD4+ T cell memory subsets. Our results suggest that AAC-11 survival pathway is potentially involved in the survival of HIV-1 infectable cells and provide a proof of principle that some cellular characteristics can be targeted to eliminate the cells offering the best conditions to sustain HIV-1 replication.IMPORTANCEAlthough antiretroviral treatment efficiently blocks HIV multiplication, it cannot eliminate the cells already carrying integrated proviruses. In the search for a HIV cure the identification of new potential targets to selectively eliminate infected cells is of the outmost importance. We show here that peptides derived from the anti-apoptotic clone 11 (AAC-11), which expression levels correlated with susceptibility to HIV-1 infection of CD4+ T-cells, induced cytotoxicity in CD4+ T-cells showing the highest levels of activation and metabolic activity, conditions known to favor HIV-1 infection. Accordingly, CD4+ T-cells that survived the cytotoxic action of the AAC-11 peptides were resistant to HIV-1 replication. Our results identify a new potential molecular pathway to target HIV-1 infection.

show abstract

Section: Resultssupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Anti-apoptotic clone 11 derived peptides induce in vitro death of CD4+ T cells susceptible to HIV-1 infection

Mikhailova

Valle-Casuso

David

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…There are few scientific reports on the use of synthetic peptides that can induce ICD 45‐47 . Herein, we assessed the ability of PKHB1, the first serum‐stable CD47‐agonist peptide: (i) to induce selective cell death in T‐ALL cells with conserved characteristics of CD47‐mediated cell death; and (ii) to determine whether this type of cell death is immunogenic.…”

Section: Discussionmentioning

confidence: 99%

“…There are few scientific reports on the use of synthetic peptides that can induce ICD. [45][46][47] Herein, we assessed the ability of PKHB1, the first serum-stable CD47-agonist peptide: (i) to induce selective cell death in T-ALL cells with conserved characteristics of CD47mediated cell death; and (ii) to determine whether this type of cell death is immunogenic. We observed that PKHB1 induced death in CEM, MOLT-4, and L5178Y-R cells (Figure 1), in a fast caspaseindependent process that implicates phosphatidylserine exposure along with plasma membrane permeabilization, and loss of mitochondrial membrane potential (Figure 2) that is selective for malignant cells (Figure 3).…”

Section: Discussionmentioning

confidence: 99%

CD47 agonist peptide PKHB1 induces immunogenic cell death in T‐cell acute lymphoblastic leukemia cells

et al. 2018

View full text Add to dashboard Cite

T‐cell acute lymphoblastic leukemia (T‐ALL) has a poor prognosis derived from its genetic heterogeneity, which translates to a high chemoresistance. Recently, our workgroup designed thrombospondin‐1‐derived CD47 agonist peptides and demonstrated their ability to induce cell death in chronic lymphocytic leukemia. Encouraged by these promising results, we evaluated cell death induced by PKHB1 (the first‐described serum‐stable CD47‐agonist peptide) on CEM and MOLT‐4 human cell lines (T‐ALL) and on one T‐murine tumor lymphoblast cell‐line (L5178Y‐R), also assessing caspase and calcium dependency and mitochondrial membrane potential. Additionally, we evaluated selectivity for cancer cell lines by analyzing cell death and viability of human and murine non‐tumor cells after CD47 activation. In vivo, we determined that PKHB1‐treatment in mice bearing the L5178Y‐R cell line increased leukocyte cell count in peripheral blood and lymphoid organs while recruiting leukocytes to the tumor site. To analyze whether CD47 activation induced immunogenic cell death (ICD), we evaluated damage‐associated molecular patterns (DAMP) exposure (calreticulin, CRT) and release (ATP, heat shock proteins 70 and 90, high‐mobility group box 1, CRT). Furthermore, we gave prophylactic antitumor vaccination, determining immunological memory. Our data indicate that PKHB1 induces caspase‐independent and calcium‐dependent cell death in leukemic cells while sparing non‐tumor murine and human cells. Moreover, our results show that PKHB1 can induce ICD in leukemic cells as it induces CRT exposure and DAMP release in vitro, and prophylactic vaccinations inhibit tumor establishment in vivo. Together, our results improve the knowledge of CD47 agonist peptides potential as therapeutic tools to treat leukemia.

show abstract

“…In LXR agonist-treated Balb/c mice, CRT and HMGB1 expression levels were increased and the LXR agonists exhibited tumour vaccine effects by inducing ICD. 51 Similarly, the oncolytic peptides RT53 and LTX-315 also trigger the exposure of CRT and the release of HGMB1 and ATP as obligatory signals for ICD [48][49][50] ; however, concerning the induction mechanism, and triggering classic immunogenic cell death. Mitochondrial outer membrane permeabilization (MOMP) is another factor that stimulates NF-κB activity and subsequently induces caspase-independent cell death (CICD), which is also regarded as ICD…”

Section: Conclusion and Further Perspec Tivesmentioning

confidence: 99%

Immunogenic cell death in cancer therapy: Present and emerging inducers

Zhou

Wang

Chen

et al. 2019

J Cellular Molecular Medi

548

358

View full text Add to dashboard Cite

In the tumour microenvironment (TME), immunogenic cell death (ICD) plays a major role in stimulating the dysfunctional antitumour immune system. Chronic exposure of damage‐associated molecular patterns (DAMPs) attracts receptors and ligands on dendritic cells (DCs) and activates immature DCs to transition to a mature phenotype, which promotes the processing of phagocytic cargo in DCs and accelerates the engulfment of antigenic components by DCs. Consequently, via antigen presentation, DCs stimulate specific T cell responses that kill more cancer cells. The induction of ICD eventually results in long‐lasting protective antitumour immunity. Through the exploration of ICD inducers, recent studies have shown that there are many novel modalities with the ability to induce immunogenic cancer cell death. In this review, we mainly discussed and summarized the emerging methods for inducing immunogenic cancer cell death. Concepts and molecular mechanisms relevant to antitumour effects of ICD are also briefly discussed.

show abstract

The anticancer peptide RT53 induces immunogenic cell death

Cited by 50 publications

References 58 publications

Anti-apoptotic clone 11 derived peptides induce in vitro death of CD4+ T cells susceptible to HIV-1 infection

Anti-apoptotic clone 11 derived peptides induce in vitro death of CD4+ T cells susceptible to HIV-1 infection

CD47 agonist peptide PKHB1 induces immunogenic cell death in T‐cell acute lymphoblastic leukemia cells

Immunogenic cell death in cancer therapy: Present and emerging inducers

Contact Info

Product

Resources

About