Abstract
BackgroundHepatocellular carcinoma (HCC) is one of the most common cancers in the world which is highly chemoresistant to currently available chemotherapeutic agents. Thus, novel therapeutic targets are needed to be sought for the successful treatment of HCC. Peptaibols, a family of peptides synthesized non-ribosomally by the Trichoderma species and other fungi, exhibit antibiotic activities against bacteria and fungi. Few studies recently showed that peptaibols exerted cytotoxicity toward human lung epithelial and breast carcinoma cells. However, the mechanism involved in peptaibol-induced cell death remains poorly understood.ResultsHere, we showed that Trichokonin VI (TK VI), a peptaibol from Trichoderma pseudokoningii SMF2, induced growth inhibition of HCC cells in a dose-dependent manner. It did not obviously impair the viability of normal liver cells at lower concentration. Moreover, the suppression of cell viability resulted from the programmed cell death (PCD) with characteristics of apoptosis and autophagy. An influx of Ca2+ triggered the activation of μ-calpain and proceeded to the translocation of Bax to mitochondria and subsequent promotion of apoptosis. On the other hand, typically morphological characteristics consistent with autophagy were also observed by punctate distribution of MDC staining and the induction of LC3-II, including extensive autophagic vacuolization and enclosure of cell organelles by these autophagosomes. More significantly, specific depletion of Bak expression by small RNA interfering (siRNA) could partly attenuate TK VI-induced autophagy. However, siRNA against Bax led to increased autophagy.ConclusionTaken together, these findings showed for the first time that peptaibols were novel regulators involved in both apoptosis and autophagy, suggesting that the class of peptaibols might serve as potential suppressors of tumor cells.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common cancers in the world which is highly chemoresistant to currently available chemotherapeutic agents
Trichokonin VI (TK VI) predisposed cancer cells to apoptosis accompanied by morphological changes compatible with autophagy To assess whether TK VI induced cell death, MTT assay was used to measure the relative survival of cells
When BGC-823, A549 and HepG2 cells were incubated with increasing concentrations of TK VI, TK VI and etoposide caused a dose-dependent inhibition of cell proliferation, whereas the inhibitory effect of TK VI was approximately two-fold higher than that of etoposide with concentrations ranging from 30 to 40 μM (Figure. 1A)
Summary
Hepatocellular carcinoma (HCC) is one of the most common cancers in the world which is highly chemoresistant to currently available chemotherapeutic agents. The mechanism involved in peptaibol-induced cell death remains poorly understood. Hepatocellular carcinoma is the fifth most common solid tumor worldwide and the fourth leading cause of cancer-related death. The majority of tumors initially respond to chemotherapy, hepatocellular carcinoma is well known for its expression of the multidrug resistance gene and its poor response to currently available chemotherapeutic agents [1,2]. Peltola [10] reported that the peptaibols from Trichoderma harzianum suppressed the growth of A549 cells and dissipated the mitochondrial membrane potential (ΔΨm). The precise mechanism and the basic components in cellular death pathway involved in peptaibol are currently unknown
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