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ABSTRACT
Our previous study revealed 11’-deoxyverticillin A (C42), a natural product isolated from the Ophiocordyceps-associated fungus Clonostachys rogersoniana and a member of the epipolythiodioxopiperazines (ETPs), induced both apoptosis and autophagy in HCT116 cells; however, the role of disulphide/polysulphide bridges of C42 in the regulation of autophagy remains unexplored. Here, we revealed that C42 activated both caspase-dependent apoptosis and autophagy in HeLa cells, whereas its disulphide cleavage derivative C42-4 failed to induce the cleavage of both caspase-3 and PARP-1. In contrast, both C42 and C42-4 increased the formation of autophagosomes, punctate staining of LC3, and the ratio of LC3-II to actin, suggesting that disulphide/polysulphide bridges are dispensable for the induction of the autophagic process. Moreover, we found that C42 but not C42-4 led to nuclear instability by increasing the formation of micronuclei and expression of phosphorylated histone H2AX (γ-H2AX), a widely used marker for DNA double strand breaks (DSBs), while Rad51, a protein pivotal for DNA repair, was decreased upon challenge with C42. These results demonstrate that the disulphide bonds in ETPs play an essential role in the induction of caspase-dependent apoptosis and nuclear stability.
GRAPHICAL ABSTRACT
Acknowledgments
We thank Dr. Yongsheng Che (Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China) for kindly providing C42.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Supplemental data
Supplemental data for this article can be accessed online at https://doi.org/10.1080/21501203.2023.2248168