Calcium-Dependent Calpain Activation-Mediated Mitochondrial Dysfunction and Oxidative Stress Are Required for Cytotoxicity of Epinecidin-1 in Human Synovial Sarcoma SW982 Cells

Abstract

Synovial sarcoma is a rare but highly malignant and metastatic disease. Despite its relative sensitivity to chemotherapies, the high recurrence and low 5-year survival rate for this disease suggest that new effective therapeutic agents are urgently needed. Marine antimicrobial peptide epinecidin-1 (epi-1), which was identified from orange-spotted grouper (Epinephelus coioides), exhibits multiple biological effects, including bactericidal, immunomodulatory, and anticancer activities. However, the cytotoxic effects and mechanisms of epi-1 on human synovial sarcoma cells are still unclear. In this study, we report that epi-1 exhibits prominent antisynovial sarcoma activity in vitro and in a human SW982 synovial sarcoma xenograft model. Furthermore, we determined that calcium overload-induced calpain activation and subsequent oxidative stress and mitochondrial dysfunction are required for epi-1-mediated cytotoxicity. Interestingly, reactive oxygen species (ROS)-mediated activation of extracellular signal-regulated kinase (ERK) plays a protective role against epi-1-induced cytotoxicity. Our results provide insight into the molecular mechanisms underlying epi-1-induced cell death in human SW982 cells.

Marine Antimicrobial Peptide TP4 Exerts Anticancer Effects on Human Synovial Sarcoma Cells via Calcium Overload, Reactive Oxygen Species Production and Mitochondrial Hyperpolarization

“…Cell shrinkage was observed after exposure to TP4 or stausporine; however, only exposure to TP4 increased the percentage of cells with incorporated PI (Figure 2A). Release of cyclophilin A into culture supernatant can serve as a marker for necrotic cell death [22,26], and we found that TP4 increased cyclophilin A in the supernatant, but not the apoptotic marker, caspase-3, in the lysate (Figure 2B). Furthermore, both GSK'872 and Necrostain-1 (necrotic inhibitors) effectively suppressed TP4-induced cytotoxicity in SW982 (Figure 2C,D) and Aska-SS cells (Figure 2E,F).…”

“…The Aska-SS human synovial sarcoma cell line was purchased from RIKEN BioResource Research Center (Koyadai, Ibaraki, Japan). SW982 cells were cultured as described previously [ 26 ]. Aska-SS cells were maintained in Dulbecco’s Modified Eagle’s medium (DMEM; ThermoFisher), supplemented with 20% fetal bovine serum (Biological Industries; Cromwell, CT, USA) and penicillin-streptomycin (Biological Industries; Cromwell, CT, USA).…”

Recurrent primary intracranial synovial sarcoma, a case report and review of the literature

“…22 This issue has been found specifically in SSs. 23 Besides, considering the 75% expression of PD-L1 on SS cells, one might assume that this modality might be applied in the future for primary intracranial SSs. 24 Current literature has noted that the immunotherapy results can be improved by improving mitochondria biogenesis.…”

“…In addition, the current understanding of cancer cells has highlighted the importance of mitochondria in cancer biogenesis 22 . This issue has been found specifically in SSs 23 . Besides, considering the 75% expression of PD‐L1 on SS cells, one might assume that this modality might be applied in the future for primary intracranial SSs 24 .…”

Inhibition of Calpain Alleviates Apoptosis in Coxsackievirus B3-induced Acute Virus Myocarditis Through Suppressing Endoplasmic Reticulum Stress

“…36) Excessive calcium induces calpain activation. 37) Therefore, we hypothesized that CVB3 infection could activate calpain. In our previous studies, we have demonstrated that calpain was activated during CVB3 infection.…”