Abstract
Gliotoxin, a secondary metabolite produced by marine fungus Aspergillus sp., possesses various biological activities including anticancer activity. However, the mechanism underlying gliotoxin-induced cytotoxicity on human cervical cancer (Hela) and human chondrosarcoma (SW1353) cells remains unclear. In this study, we focused on the effect of gliotoxin induction on apoptosis, the activating expressions of caspase family enzymes in the cells. Apoptotic cell levels were measured through DAPI and Annexin V/Propidium Iodide (PI) double staining analysis. The apoptotic protein expression of Bcl-2 and caspase family was detected by Western blot in Hela and SW1353 cells. Our results showed that gliotoxin treatment inhibited cell proliferation and induced significant morphological changes. Gliotoxin induced apoptosis was further confirmed by DNA fragmentation, chromatin condensation and disrupted mitochondrial membrane potential. Gliotoxin-induced activation of caspase-3, caspase-8 and caspase-9, down-regulation of Bcl-2, up-regulation of Bax and cytochromec (cyt c) release showed evidence for the gliotoxin activity on apoptosis. These findings suggest that gliotoxin isolated from marine fungus Aspergillus sp. induced apoptosis in Hela and SW1353 cells via the mitochondrial pathway followed by downstream events leading to apoptotic mode of cell death.
Highlights
Apoptosis, a major form of cell death, is characterized by several unique features, including cell shrinkage, nuclear collapse, membrane blebbing, and internucleosomal DNA cleavage (DNA fragmentation) [1,2]
Because the appearance of apoptotic bodies is regarded as the apoptotic hallmark, the results suggested that gliotoxin induced the death of human cervical cancer (Hela) and SW1353 cells mainly through apoptosis
The data reveal that HeLa and SW1353 cells are highly sensitive to growth inhibition and apoptosis induction by gliotoxin
Summary
A major form of cell death, is characterized by several unique features, including cell shrinkage, nuclear collapse, membrane blebbing, and internucleosomal DNA cleavage (DNA fragmentation) [1,2]. Programmed cell death plays critical roles in a wide variety of physiologic processes during fetal development and in adult tissues [3]. Defects in apoptosis facilitate tumor progression, by rendering cancer cells resistant to death mechanisms relevant to metastasis, growth factor deprivation and chemotherapy [4]. Two apoptotic pathways are known as the intrinsic (death receptor-mediated) and the extrinsic (mitochondrial-mediated) pathway [1]. Mitochondria play a key role in mediating apoptosis; opening of the permeability transition pore and a subsequent drop in mitochondrial membrane potential (ΔΨm) have been suggested as the main mechanisms [2]. Loss of ΔΨm leads to the release of cytochrome c (cyt c) from mitochondria, leading to the activation of caspase-9 and further activating the downstream effector caspase-3 [5]
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