The Antimicrobial Peptide γ-Thionin from Habanero Chile ( Capsicum chinense ) Induces Caspase-Independent Apoptosis on Human K562 Chronic Myeloid Leukemia Cells and Regulates Epigenetic Marks

• Published in: Molecules (Basel, Switzerland) Switzerland), 2023-04, Vol.28 (9), p.3661
• Main Authors: Flores-Alvarez, Luis José, Jiménez-Alcántar, Paola, Ochoa-Zarzosa, Alejandra, López-Meza, Joel E
• Format: Article
• Language: English
• Subjects: Acetylation; Animals; Antiinfectives and antibacterials; Antimicrobial Peptides; Antineoplastic Agents - pharmacology; Apoptosis; Calcium (intracellular); calpains; Cancer; Capsicum - chemistry; Capsicum chinense; Caspase; Caspases - metabolism; Cell activation; Chile; Chromatin; Chronic myeloid leukemia; Cytotoxicity; Defensins; Defensins - pharmacology; Epigenesis, Genetic; Epigenetic inheritance; epigenetic regulation; Epigenetics; Histones; Humans; K562 Cells; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukocytes (mononuclear); Leukocytes, Mononuclear - metabolism; Lysine; Lysine - pharmacology; Membrane potential; Membranes; Methylation; Mitochondria; Myeloid leukemia; Peptides; Peptides - pharmacology; Peripheral blood mononuclear cells; Phosphorylation; Thionins - pharmacology; Tumor necrosis factor-TNF; γ-thionin
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules28093661

Cancer is a relevant health problem worldwide. In 2020, leukemias represented the 13th most commonly reported cancer cases worldwide but the 10th most likely to cause deaths. There has been a progressive increase in the efficacy of treatments for leukemias; however, these still generate important side effects, so it is imperative to search for new alternatives. Defensins are a group of antimicrobial peptides with activity against cancer cells. However, the cytotoxic mechanism of these peptides has been described mainly for animal defensins. This study shows that defensin γ-thionin ( ) is cytotoxic to the K562 leukemia cells with an IC = 290 μg/mL (50.26 μM) but not for human peripheral blood mononuclear cells. Results showed that γ-thionin did not affect the membrane potential; however, the peptide modified the mitochondrial membrane potential (ΔΨm) and the intracellular calcium release. In addition, γ-thionin induced apoptosis in K562 cells, but the activation of caspases 8 and 9 was not detected. Moreover, the activation of calpains was detected at one hour of treatment, suggesting that γ-thionin activates the caspase-independent apoptosis. Furthermore, the γ-thionin induced epigenetic modifications on histone 3 in K562 cells, increased global acetylation (~2-fold), and specific acetylation marks at lysine 9 (H3K9Ac) (~1.5-fold). In addition, γ-thionin increased the lysine 9 methylation (H3K9me) and dimethylation marks (H3K9me2) (~2-fold), as well as the trimethylation mark (H3K9me3) (~2-fold). To our knowledge, this is the first report of a defensin that triggers caspase-independent apoptosis in cancer cells via calpains and regulating chromatin remodelation, a novel property for a plant defensin.