Transient Receptor Potential C 1/4/5 Is a Determinant of MTI-101 Induced Calcium Influx and Cell Death in Multiple Myeloma

Multiple myeloma (MM) is a currently incurable hematologic cancer. Patients that initially respond to therapeutic intervention eventually relapse with drug resistant disease. Thus, novel treatment strategies are critically needed to improve patient outcomes. Our group has developed a novel cyclic peptide referred to as MTI-101 for the treatment of MM. We previously reported that acquired resistance to HYD-1, the linear form of MTI-101, correlated with the repression of genes involved in store operated Ca2+ entry (SOCE): PLCβ, SERCA, ITPR3, and TRPC1 expression. In this study, we sought to determine the role of TRPC1 heteromers in mediating MTI-101 induced cationic flux. Our data indicate that, consistent with the activation of TRPC heteromers, MTI-101 treatment induced Ca2+ and Na+ influx. However, replacing extracellular Na+ with NMDG did not reduce MTI-101-induced cell death. In contrast, decreasing extracellular Ca2+ reduced both MTI-101-induced Ca2+ influx as well as cell death. The causative role of TRPC heteromers was established by suppressing STIM1, TRPC1, TRPC4, or TRPC5 function both pharmacologically and by siRNA, resulting in a reduction in MTI-101-induced Ca2+ influx. Mechanistically, MTI-101 treatment induces trafficking of TRPC1 to the membrane and co-immunoprecipitation studies indicate that MTI-101 treatment induces a TRPC1-STIM1 complex. Moreover, treatment with calpeptin inhibited MTI-101-induced Ca2+ influx and cell death, indicating a role of calpain in the mechanism of MTI-101-induced cytotoxicity. Finally, components of the SOCE pathway were found to be poor prognostic indicators among MM patients, suggesting that this pathway is attractive for the treatment of MM.

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New Insights on the Role of TRP Channels in Calcium Signalling and Immunomodulation: Review of Pathways and Implications for Clinical Practice

Clinical Reviews in Allergy & Immunology ◽

10.1007/s12016-020-08824-3 ◽

2021 ◽

Author(s):

Saied Froghi ◽

Charlotte R. Grant ◽

Radhika Tandon ◽

Alberto Quaglia ◽

Brian Davidson ◽

...

Keyword(s):

Immune System ◽

Calcium Release ◽

Transient Receptor Potential ◽

Trp Channels ◽

Calcium Influx ◽

Calcium Signalling ◽

Chronic Fatigue ◽

Diverse Range ◽

Immune System Activation

AbstractCalcium is the most abundant mineral in the human body and is central to many physiological processes, including immune system activation and maintenance. Studies continue to reveal the intricacies of calcium signalling within the immune system. Perhaps the most well-understood mechanism of calcium influx into cells is store-operated calcium entry (SOCE), which occurs via calcium release-activated channels (CRACs). SOCE is central to the activation of immune system cells; however, more recent studies have demonstrated the crucial role of other calcium channels, including transient receptor potential (TRP) channels. In this review, we describe the expression and function of TRP channels within the immune system and outline associations with murine models of disease and human conditions. Therefore, highlighting the importance of TRP channels in disease and reviewing potential. The TRP channel family is significant, and its members have a continually growing number of cellular processes. Within the immune system, TRP channels are involved in a diverse range of functions including T and B cell receptor signalling and activation, antigen presentation by dendritic cells, neutrophil and macrophage bactericidal activity, and mast cell degranulation. Not surprisingly, these channels have been linked to many pathological conditions such as inflammatory bowel disease, chronic fatigue syndrome and myalgic encephalomyelitis, atherosclerosis, hypertension and atopy.

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Pursuing a Curative Approach in Multiple Myeloma: A Review of New Therapeutic Strategies

Cancers ◽

10.3390/cancers11122015 ◽

2019 ◽

Vol 11 (12) ◽

pp. 2015 ◽

Cited By ~ 9

Author(s):

Mattia D'Agostino ◽

Luca Bertamini ◽

Stefania Oliva ◽

Mario Boccadoro ◽

Francesca Gay

Keyword(s):

Multiple Myeloma ◽

Residual Disease ◽

Treatment Strategies ◽

Progression Free Survival ◽

Hematologic Cancer ◽

Focus On Results ◽

Individualize Treatment ◽

New Generation ◽

Effective Drugs

Multiple myeloma (MM) is still considered an incurable hematologic cancer and, in the last decades, the treatment goal has been to obtain a long-lasting disease control. However, the recent availability of new effective drugs has led to unprecedented high-quality responses and prolonged progression-free survival and overall survival. The improvement of response rates has prompted the development of new, very sensitive methods to measure residual disease, even when monoclonal components become undetectable in patients’ serum and urine. Several scientific efforts have been made to develop reliable and validated techniques to measure minimal residual disease (MRD), both within and outside the bone marrow. With the newest multidrug combinations, a good proportion of MM patients can achieve MRD negativity. Long-lasting MRD negativity may prove to be a marker of “operational cure”, although the follow-up of the currently ongoing studies is still too short to draw conclusions. In this article, we focus on results obtained with new-generation multidrug combinations in the treatment of high-risk smoldering MM and newly diagnosed MM, including the potential role of MRD and MRD-driven treatment strategies in clinical trials, in order to optimize and individualize treatment.

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Integrin α10, a Novel Therapeutic Target in Glioblastoma, Regulates Cell Migration, Proliferation, and Survival

Cancers ◽

10.3390/cancers11040587 ◽

2019 ◽

Vol 11 (4) ◽

pp. 587 ◽

Cited By ~ 8

Author(s):

Matilda Munksgaard Thorén ◽

Katarzyna Chmielarska Masoumi ◽

Cecilia Krona ◽

Xiaoli Huang ◽

Soumi Kundu ◽

...

Keyword(s):

Cell Death ◽

Therapeutic Target ◽

Functional Role ◽

Treatment Strategies ◽

Antibody Drug Conjugate ◽

Potential Therapeutic Target ◽

Sphere Formation

New, effective treatment strategies for glioblastomas (GBMs), the most malignant and invasive brain tumors in adults, are highly needed. In this study, we investigated the potential of integrin α10β1 as a therapeutic target in GBMs. Expression levels and the role of integrin α10β1 were studied in patient-derived GBM tissues and cell lines. The effect of an antibody–drug conjugate (ADC), an integrin α10 antibody conjugated to saporin, on GBM cells and in a xenograft mouse model was studied. We found that integrin α10β1 was strongly expressed in both GBM tissues and cells, whereas morphologically unaffected brain tissues showed only minor expression. Partial or no overlap was seen with integrins α3, α6, and α7, known to be expressed in GBM. Further analysis of a subpopulation of GBM cells selected for high integrin α10 expression demonstrated increased proliferation and sphere formation. Additionally, siRNA-mediated knockdown of integrin α10 in GBM cells led to decreased migration and increased cell death. Furthermore, the ADC reduced viability and sphere formation of GBM cells and induced cell death both in vitro and in vivo. Our results demonstrate that integrin α10β1 has a functional role in GBM cells and is a novel, potential therapeutic target for the treatment of GBM.

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Anti-Leukemia and Multiple Myeloma Selective Activity of CXCR4 Antagonist 4F-Benzoyl-TN14003 Involves Apoptotic Death Pathway.

Blood ◽

10.1182/blood.v114.22.3857.3857 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3857-3857

Author(s):

Katia Beider ◽

Michal Begin ◽

Michal Abraham ◽

Hanna Wald ◽

Ido Weiss ◽

...

Keyword(s):

Multiple Myeloma ◽

Cell Death ◽

Hematological Malignancies ◽

Conflicts Of Interest ◽

K562 Cells ◽

Jurkat Cells ◽

G1 Arrest ◽

Dependent Manner ◽

Hl60 Cells

Abstract Abstract 3857 Poster Board III-793 The chemokine receptor CXCR4 and its ligand CXCL12 are involved in the development and progression of a diverse number of hematological malignancies, including leukemia, lymphoma and multiple myeloma (MM). Binding CXCL12 to CXCR4 activates a variety of intracellular signal transduction pathways and effector molecules that regulate cell chemotaxis, adhesion, survival, apoptosis and proliferation. It was previously shown that CXCR4 signaling can directly induce caspase-independent cell apoptosis through the interaction with the HIV gp120 envelope protein. In the present study we investigated the effect of CXCR4 specific antagonists 4F-benzoyl-TN14003 (T140) and AMD3100 on the survival and proliferation of different human hematological cancer cells. Here, we demonstrate that T140, but not AMD3100, exhibits preferential cytotoxicity towards malignant cells of hematopoietic origin, as compared to primary normal cells or solid prostate and breast tumor cells. The in vitro treatment with T140, but not with AMD3100, significantly decreased the number of viable chronic myeloid leukemia K562 cells, acute T cell leukemia Jurkat cells, acute promyelocytic leukemia NB4 and HL60 cells, and four different MM cell lines (U266, NCI-H929, RPMI8226 and ARH77), demonstrating the highest sensitivity to T140 (p<0.01). Notably, T140 inhibited the growth of freshly isolated leukemia and MM cells obtained from consenting patients. T140 inhibits the growth of MM and leukemic cells by inducing their apoptotic cell death. The apoptotic changes in the cells were associated with morphological changes, phosphatidylserine externalization, sub-G1 arrest, DNA double-stranded breaks, decrease in mitochondrial membrane potential, release of cytochrome c, and caspase 3 activation. The important role of CXCR4 in T140-mediated cell death was confirmed by demonstrating that CXCR4 over-expression in NB4 and K562 cells increased their sensitivity to T140. Furthermore, pretreatment of NB4 and HL60 cells with AMD3100 abolishes the effect of T140 on these cells, indicating the involvement of CXCR4 in T140-induced apoptosis. Importantly, the combination with novel anti-myeloma agent bortezomib significantly augments anti-myeloma activity of T140. The anti leukemic and MM effect of T140 was confirmed in xenograft in vivo tumor models. Subcutaneous (s.c.) or intra-peritoneal (i.p.) injections of T140 (100 or 300 mcg/mouse) significantly reduced, in a dose-dependent manner, the tumor size in immuno-deficient mice that were previously inoculated s.c. with human acute leukemia cells NB4 or MM cells RPMI8226 (p<0.01). Tumors from animals treated with T140 had smaller sizes and weights, larger necrotic areas and high apoptotic scores. Taken together, these data support the unique anti-cancer effect of T140 in hematological malignancies and indicate the potential therapeutic role of T140 in MM and leukemia patients. Disclosures: No relevant conflicts of interest to declare.

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Delineating CDK9 Regulated Molecular Events for the Development of Rationally Derived Multiple Myeloma Treatment Strategies

Blood ◽

10.1182/blood-2021-149254 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1598-1598

Author(s):

Osman Aksoy ◽

Judith Lind ◽

Vincent Sunder-Plassmann ◽

Martin Percherstorfer ◽

Sonia Vallet ◽

...

Keyword(s):

Multiple Myeloma ◽

Tumor Microenvironment ◽

Tumor Cell ◽

Treatment Strategies ◽

Loss Of Function ◽

Rna Pol Ii ◽

Pol Ii ◽

Protein Levels ◽

Molecular Events

Abstract Background: Despite major advances in multiple myeloma (MM) therapy over the last 2 decades, most patients relapse. The identification of novel targets and the development of derived treatment approaches are therefore urgently needed. Aberrant expression of various cyclin-dependent kinases (CDKs) in solid and hematologic malignancies including MM, results in the loss of proliferative control and enhanced survival. The serine-threonine kinase CDK9, a subunit of pTEFb, in particular, is a major transcriptional regulator of numerous oncogenes. Past studies have suggested CDK9 as a potential therapeutic target in MM. However, CDK9-regulated molecular events in MM are only partly understood. By delineating CDK9-dependent pathophysiologic effects, the present study proposes rationally derived anti-CDK9-containing novel MM treatment strategies to improve patient outcome. Methods: Following expression profiling, CRISPR loss-of-function screens and correlation analyses in MM cell line and patient cells, the regulatory impact of CDK9 on downstream target genes was outlined using genomic as well as pharmacological approaches in 2D/3D MM models of the tumor microenvironment. Functionally, CDK9-regulated molecular effects as well as anti-MM activity of anti-CDK9-containing rationally derived treatment combinations were determined by gene arrays, qPCR, flow cytometry, and western blot, proliferation and survival analyses. Results: Strongly suggested by a significant induction of CDK9 mRNA expression levels progressing from normal plasma cells to cells from patients with MGUS, SMM and MM; siRNA and CRISP loss-of-function screens across various MM cell lines verified their dependency on CDK9. Correlative expression levels indicated a functional role of CDK9 (but not for CDK2 and CDK7) on Mcl-1, cMyc, Mdm2, RNA Pol II, and IRF4, but not other genes (e.g. Bcl-2) in the CCLE as well as CoMMpass and GSE5900/GSE2658 MM patient datasets. Indeed, siRNA-mediated CDK9 silencing decreased protein levels of Mcl-1, cMyc, Mdm2, RNA Pol II, and IRF4, and consequently tumor cell survival. Similarly, the novel, selective CDK9-directed proteolysis-targeting chimera Thal-sns-032 induced a reduction of mRNA/ protein levels of Mcl-1, cMyc, RNA Pol II, but not of other potential targets (e.g. Bcl-2) in a dose- and time-dependent manner. Moreover, Thal-sns-032 reduced Mdm2 and thereby increased p53 protein levels. Consequently, Thal-sns-032 inhibited tumor cell proliferation and survival both in tumor cell- and tumor cell:BMSC co- cultures. Rationally, derived combination strategies of Thal-sns-032 for example with venetoclax, but also other investigational and established MM therapies induced synergistic anti-MM effects within the tumor microenvironment. Conclusion: In summary, by delineating CDK9-regulated molecular events in MM, our studies strongly support the therapeutic role of targeted CDK9-therapy and rationally derive MM combination treatment strategies. Disclosures Vallet: Pfizer: Honoraria; MSD: Honoraria; Roche Pharmaceuticals: Consultancy. Podar: Celgene: Consultancy, Honoraria; Amgen Inc.: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Roche Pharmaceuticals: Research Funding.

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Investigating the Role of Chromatin Remodeler FOXA1 in Ferroptotic Cell Death

10.1101/2021.10.13.461056 ◽

2021 ◽

Author(s):

Emilie Logie ◽

Louis Maes ◽

Joris Van Meenen ◽

Peter HL De Rijk ◽

Mojca Strazisar ◽

...

Keyword(s):

Lipid Peroxidation ◽

Multiple Myeloma ◽

Dna Damage ◽

Cell Death ◽

Transcription Factor ◽

Signaling Pathways ◽

Chromatin Remodeler ◽

Myeloma Cells ◽

Foxa1 Expression

Ferroptosis is a lipid peroxidation-dependent mechanism of regulated cell death known to suppress tumor proliferation and progression. Although several genetic and protein hallmarks have been identified in ferroptotic cell death, it remains challenging to fully characterize ferroptosis signaling pathways and to find suitable biomarkers. Moreover, changes taking place in the epigenome of ferroptotic cells remain poorly studied. In this context, we aimed to investigate the role of chromatin remodeler forkhead box protein A1 (FOXA1) in RSL3-treated multiple myeloma cells because, similar to ferroptosis, this transcription factor has been associated with changes in the lipid metabolism, DNA damage, and epithelial-to-mesenchymal transition (EMT). RNA sequencing and Western blot analysis revealed that FOXA1 expression is consistently upregulated upon ferroptosis induction in different in vitro and in vivo disease models. In silico motif analysis and transcription factor enrichment analysis further suggested that ferroptosis-mediated FOXA1 expression is orchestrated by specificity protein 1 (Sp1), a transcription factor known to be influenced by lipid peroxidation. Remarkably, FOXA1 upregulation in ferroptotic myeloma cells did not alter hormone signaling or EMT, two key downstream signaling pathways of FOXA1. CUT&RUN genome-wide transcriptional binding site profiling showed that GPX4-inhibition by RSL3 triggered loss of binding of FOXA1 to pericentromeric regions in multiple myeloma cells, suggesting that this transcription factor is possibly involved in genomic instability, DNA damage, or cellular senescence under ferroptotic conditions.

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Abstract A019: Role of MTI-101 in disrupting calcium homeostasis leading to cell death in multiple myeloma

10.1158/1535-7163.targ-19-a019 ◽

2019 ◽

Author(s):

Osama M Elzamzamy ◽

Karen Hayes ◽

Werner Geldenhuys ◽

Lori A Hazlehurst

Keyword(s):

Multiple Myeloma ◽

Cell Death ◽

Calcium Homeostasis

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Displacement of Bim From Anti-Apoptotic Proteins Is the Primary Factor for Determining ABT-737 Activity in Multiple Myeloma Cell Lines.

Blood ◽

10.1182/blood.v114.22.2851.2851 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2851-2851

Author(s):

Alejo A Morales ◽

Metin Kurtoglu ◽

David Siefker ◽

Shannon M Matulis ◽

Delia M Gutman ◽

...

Keyword(s):

Multiple Myeloma ◽

Cell Death ◽

Cell Lines ◽

Cell Types ◽

Myeloma Cell ◽

Resistant Cell ◽

The Other ◽

Multiple Myeloma Cell ◽

Other Hand

Abstract Abstract 2851 Poster Board II-827 ABT-737 and its orally active analog ABT-263 are Bcl-2-family inhibitors that are currently in clinical trials for a variety of cancers including hematological malignancies such as multiple myeloma. Previously, we reported that the sensitivity of multiple myeloma cell lines to ABT-737 correlates with the interactions, but not the expression, of Bcl-2 proteins. Analysis of 6 multiple myeloma cell lines revealed that expression of Bcl-2 proteins did not correlate with sensitivity, however the sensitive cells (8226/S, MM.1S and KMS-11) have a substantial amount of their pro-apoptotic Bcl-2 protein, Bak, bound to Bcl-xL. On the other hand, in the insensitive cell lines (U266, KMS-11 and OPM2), Bak was found to be associated with Mcl-1, a family member that does not bind ABT-737 and thereby confers resistance to this drug. Furthermore, we also showed that release of the BH3-only protein Bim by ABT-737 from Bcl-xL and Bcl-2 also contributes to cell death in 8226/S and MM.1S. The purpose of the current study is to further investigate the role of Bim in ABT-737-induced cell death in the multiple myeloma lines. Similar to Bak, a substantial amount of Bim is bound to Bcl-xL and Bcl-2 in the ABT-737-sensitive cell lines, MM.1S and KMS-18, while in the insensitive cell lines, it is highly bound to Mcl-1. Surprisingly, in the ABT-737-sensitive 8226/S cells, Bim appears to bind to Mcl-1. However in these cells, ABT-737 treatment resulted in upregulation of Noxa, which is a BH3-only protein that binds Mcl-1 and can release Bim. Taken together these data suggest that although binding of Bim to Mcl-1 may confer resistance to ABT-737, in certain cell types this treatment could also induce Noxa expression that antagonizes Mcl-1-mediated resistance. Consistent with this hypothesis, Mcl-1 overexpression as well as knockdown of Noxa expression significantly protected 8226/S cells from ABT-737-induced cell death while they had no effect in MM.1S cells. To further demonstrate the role of Bim in ABT-737-induced cell death, ABT-resistant 8226/S, KMS-11, KMS-18 and U266 cell lines were generated. In the resistant cell lines of 8226/S and KMS-18, Bim is exclusively bound to Mcl-1, which was overexpressed as compared to the parental cells. Bak binding was not affected by acquisition of ABT-737 resistance. This result is in agreement with the findings that interaction of Bim and Mcl-1 confers resistance to ABT-737. On the other hand, in ABT-resistant U266 and KMS-11 cell lines, Bim expression was down-regulated while Mcl-1 levels were not changed. Thus, it appears that in cells where Bim is already bound to Mcl-1, further resistance is achieved by down-regulating the expression of this BH3-only protein. Overall, these results suggest that the complex interactions between Bcl-2 proteins need to be investigated in order to understand how multiple myeloma cells may respond to ABT-737 treatment. Disclosures: Boise: University of Chicago: Patents & Royalties.

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ClC5 Decreases the Sensitivity of Multiple Myeloma Cells to Bortezomib via Promoting Prosurvival Autophagy

Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics ◽

10.3727/096504017x15049221237147 ◽

2018 ◽

Vol 26 (3) ◽

pp. 421-429 ◽

Cited By ~ 7

Author(s):

Huimin Zhang ◽

Yuhui Pang ◽

Chuanbao Ma ◽

Jianying Li ◽

Huaquan Wang ◽

...

Keyword(s):

Multiple Myeloma ◽

Cell Death ◽

Small Interfering Rna ◽

Critical Role ◽

Treatment Strategies ◽

Myeloma Cell ◽

Beclin 1 ◽

Myeloma Cells ◽

Multiple Myeloma Cell ◽

Interfering Rna

Resistance to bortezomib (BZ) is the major problem that largely limits its clinical application in multiple myeloma treatment. In the current study, we investigated whether ClC5, a member of the chloride channel family, is involved in this process. The MTT assay showed that BZ treatment decreased cell viability in three multiple myeloma cell lines (ARH77, U266, and SKO-007), with IC50 values of 2.83, 4.37, and 1.91 nM, respectively. Moreover, BZ increased the conversion of LC3B-I to LC3B-II and expressions of beclin-1 and ATG5, concomitantly with a decreased p62 expression. Pharmacological inhibition of autophagy with 3-MA facilitated cell death in response to BZ treatment. Additionally, BZ increased ClC5 protein expression in ARH77, U266, and SKO-007 cells. Knockdown of ClC5 with small interfering RNA sensitized cells to BZ treatment, and upregulation of ClC5 induced chemoresistance to BZ. Furthermore, ClC5 downregulation promoted BZ-induced LC3B-I to LC3B-II conversion and beclin-1 expression, whereas overexpression of ClC5 showed the opposite results in ARH77 cells. Finally, BZ induced dephosphorylation of AKT and mTOR, which was significantly attenuated by ClC5 inhibition. However, ClC5 upregulation further enhanced AKT and mTOR dephosphorylation induced by BZ. Our study demonstrates that ClC5 induces chemoresistance of multiple myeloma cells to BZ via increasing prosurvival autophagy by inhibiting the AKT‐mTOR pathway. These data suggest that ClC5 may play a critical role in future multiple myeloma treatment strategies.

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The Elicitor Protein AsES Induces a Systemic Acquired Resistance Response Accompanied by Systemic Microbursts and Micro–Hypersensitive Responses in Fragaria ananassa

Molecular Plant-Microbe Interactions ◽

10.1094/mpmi-05-17-0121-fi ◽

2018 ◽

Vol 31 (1) ◽

pp. 46-60 ◽

Cited By ~ 15

Author(s):

Verónica Hael-Conrad ◽

Silvia Marisa Perato ◽

Marta Eugenia Arias ◽

Martín Gustavo Martínez-Zamora ◽

Pía de los Ángeles Di Peto ◽

...

Keyword(s):

Cell Death ◽

Systemic Acquired Resistance ◽

Calcium Influx ◽

Wide Spectrum ◽

Acquired Resistance ◽

Defense Responses ◽

Death Process ◽

Fragaria Ananassa ◽

Hypersensitive Cell Death ◽

Acremonium Strictum

The elicitor AsES (Acremonium strictum elicitor subtilisin) is a 34-kDa subtilisin-like protein secreted by the opportunistic fungus Acremonium strictum. AsES activates innate immunity and confers resistance against anthracnose and gray mold diseases in strawberry plants (Fragaria × ananassa Duch.) and the last disease also in Arabidopsis. In the present work, we show that, upon AsES recognition, a cascade of defense responses is activated, including: calcium influx, biphasic oxidative burst (O2⋅− and H2O2), hypersensitive cell-death response (HR), accumulation of autofluorescent compounds, cell-wall reinforcement with callose and lignin deposition, salicylic acid accumulation, and expression of defense-related genes, such as FaPR1, FaPG1, FaMYB30, FaRBOH-D, FaRBOH-F, FaCHI23, and FaFLS. All these responses occurred following a spatial and temporal program, first induced in infiltrated leaflets (local acquired resistance), spreading out to untreated lateral leaflets, and later, to distal leaves (systemic acquired resistance). After AsES treatment, macro-HR and macro–oxidative bursts were localized in infiltrated leaflets, while micro-HRs and microbursts occurred later in untreated leaves, being confined to a single cell or a cluster of a few epidermal cells that differentiated from the surrounding ones. The differentiated cells initiated a time-dependent series of physiological and anatomical changes, evolving to idioblasts accumulating H2O2 and autofluorescent compounds that blast, delivering its content into surrounding cells. This kind of systemic cell-death process in plants is described for the first time in response to a single elicitor. All data presented in this study suggest that AsES has the potential to activate a wide spectrum of biochemical and molecular defense responses in F. ananassa that may explain the induced protection toward pathogens of opposite lifestyle, like hemibiotrophic and necrotrophic fungi.

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