Osthole inhibits ovarian carcinoma cells through LC3-mediated autophagy and GSDME-dependent pyroptosis except for apoptosis

Liang, Jing; Zhou, Jianlong; Xu, Youqin; Huang, Xiaofei; Wang, Xuefei; Huang, Wenhua; Li, Hui

doi:10.1016/j.ejphar.2020.172990

Cited by 52 publications

(56 citation statements)

References 20 publications

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“…Our study further challenges this initial dogma of gasdermin activation, showing that ''apoptotically'' activated GSDME possesses an immunological role. In stark contrast with the more commonly studied context of GSDME in cancer cells as an apoptosis-topyroptosis converter (Croes et al, 2019;Ding et al, 2020;Liang et al, 2020;Yu et al, 2019), we specifically establish a causal link between GSDME cleavage and mature IL-1b release into the extracellular space following inflammasome activation independent of cell death.…”

Section: Discussioncontrasting

confidence: 61%

Gasdermin E permits interleukin-1 beta release in distinct sublytic and pyroptotic phases

Zhou

Abbott

2021

Cell Reports

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Section: Discussioncontrasting

confidence: 61%

Gasdermin E permits interleukin-1 beta release in distinct sublytic and pyroptotic phases

Zhou

Abbott

2021

Cell Reports

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“…Osthole can also induce LC3-mediated autophagy in the OC cells. Furthermore, when GSDME is highly expressed in the OC cells, it can induce cell pyroptosis mediated by caspase-3 64 .…”

Section: Assosiation Between Caspase-3 Dependent Cell Death and Cancementioning

confidence: 99%

The caspase-3/GSDME signal pathway as a switch between apoptosis and pyroptosis in cancer

et al. 2020

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Apoptosis has long been recognized as a mechanism that kills the cancer cells by cytotoxic drugs. In recent years, studies have proved that pyroptosis can also shrink tumors and inhibit cells proliferation. Both apoptosis and pyroptosis are caspase-dependent programmed cell death pathways. Cysteinyl aspartate specific proteinase-3 (Caspase-3) is a common key protein in the apoptosis and pyroptosis pathways, and when activated, the expression level of tumor suppressor gene Gasdermin E (GSDME) determines the mechanism of tumor cell death. When GSDME is highly expressed, the active caspase-3 cuts it and releases the N-terminal domain to punch holes in the cell membrane, resulting in cell swelling, rupture, and death. When the expression of GSDME is low, it will lead to the classical mechanism of tumor cell death, which is apoptosis. More interestingly, researchers have found that GSDME can also be located upstream of caspase-3, connecting extrinsic, and intrinsic apoptotic pathways. Then, promoting caspase-3 activation, and forming a self-amplifying feed-forward loop. GSDME-mediated pyroptosis is correlated with the side effects of chemotherapy and anti-tumor immunity. This article mainly reviews the caspase-3/GSDME signal pathway as a switch between apoptosis and pyroptosis in cancer, to provide new strategies and targets for cancer treatment.

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“…Previous literature reported that osthole induced cell death mainly in the form of apoptosis [18][19][20]. A recent study demonstrated that osthole induced cell death through the GSDME-dependent pyroptosis pathway [21].…”

Section: Discussionmentioning

confidence: 99%

Osthole Induces Apoptosis, Secondary Necrosis and Mitophagy Via NQO1-Mediated ROS Overproduction in HeLa Cells

Huangfu¹,

Wang²,

Yu³

et al. 2020

Preprint

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Background: Osthole is a natural coumarin which has been proved to inhibit growth of cancer cells by inducing cancer cells death, while its mechanism of anticancer remains unclearly. In our study, we found that osthole activated multiple forms of cell death including apoptosis, secondary necrosis and mitophagy in receptor interacting protein kinase (RIP) 3-deficient cervical cancer HeLa cells. Methods: Cell viability was detected by MTT assay. Cell membrane integrity was detected by LDH release assay and PI staining. Cell apoptosis and necrosis were detected by flow cytometry assay. Reactive oxygen species (ROS) was detected by DCFH-DA staining and mitochondrial membrane potential (MMP) was detected by JC-1 staining using flow cytometry. The expression of proteins was detected by western blotting assay and proteomics. Xenograft tumor model was used to evaluate the effect of osthole in vivo.Results: Our study showed osthole caused HeLa cells apoptosis and secondary necrosis, which is a phenomenon of the apoptotic cells’ plasma membrane breakdown. And when Hela cells pretreatment with Z-DEVD-FMK, an irreversible caspase-3 inhibitor, not only inhibited osthole-induced apoptosis but also necrosis. Moreover, we found that Z-DEVD-FMK reversed the effect of osthole on the induction of cleaved the N-terminal fragment of GSDME in Hela cells. Furthermore, inhibition of NAD (P) H: quinone oxidoreductase 1 (NQO1) by osthole induced the overproduction of reactive oxygen species (ROS). ROS inhibitor N-Acetyl-L-cysteine (NAC) not only reduced osthole-induced apoptosis, but also reversed its effect on the necrotic induction and the GSDME N-terminal generation. It was shown that osthole decreased mitochondrial membrane potential (MMP) and increased the expression of PTEN-induced putative kinase 1 (PINK1) and Parkin, which indicated that the activation of mitophagy induced by osthole. Meanwhile, as well as apoptosis and secondary necrosis, mitophagy was also restrained by NAC. Conclusions: In conclusion, all these data suggested that osthole induced apoptosis, secondary necrosis and mitophagy via NQO1-mediated ROS overproduction.

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Osthole inhibits ovarian carcinoma cells through LC3-mediated autophagy and GSDME-dependent pyroptosis except for apoptosis

Cited by 52 publications

References 20 publications

Gasdermin E permits interleukin-1 beta release in distinct sublytic and pyroptotic phases

Gasdermin E permits interleukin-1 beta release in distinct sublytic and pyroptotic phases

The caspase-3/GSDME signal pathway as a switch between apoptosis and pyroptosis in cancer

Osthole Induces Apoptosis, Secondary Necrosis and Mitophagy Via NQO1-Mediated ROS Overproduction in HeLa Cells

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