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Abstract Title:

Morusin induces paraptosis-like cell death through mitochondrial calcium overload and dysfunction in epithelial ovarian cancer.

Abstract Source:

Chem Biol Interact. 2018 Mar 1 ;283:59-74. Epub 2018 Feb 5. PMID: 29421517

Abstract Author(s):

Jing Xue, Rui Li, Xinrui Zhao, Congcong Ma, Xin Lv, Lidong Liu, Peishu Liu

Article Affiliation:

Jing Xue

Abstract:

Epithelial ovarian cancer (EOC) is the leading cause of death among all gynecological cancers. Morusin, a prenylated flavonoid extracted from the root bark of Morus australis, has been reported to exhibit anti-tumor activity against various human cancers except EOC. In the present study, we explored the potential anti-cancer activity of morusin against EOC in vitro and in vivo and possible underlying mechanisms for the first time. We first found that morusin effectively inhibited EOC cell proliferation and survival in vitro and suppressed tumor growth in vivo. Then we observed that treatment of EOC cells with morusin resulted in paraptosis-like cell death, a novel mode of non-apoptotic programmed cell death that is characterized by extensive cytoplasmic vacuolation due to dilation of the endoplasmic reticulum (ER) and mitochondria and lack of apoptotic hallmarks. In addition, we discovered that morusin induced obvious increase in mitochondrial Calevels, accumulation of ER stress markers, generation of reactive oxygen species (ROS), and loss of mitochondrial membrane potential (Δψm) in EOC cells. Furthermore, pretreatment with 4, 4'-diisothiocyanostilbene-2, 2'-disulfonic acid (DIDS), a chemical inhibitor of voltage-dependent anion channel (VDAC) on the outer mitochondrial membrane, effectively inhibited mitochondrial Cainflux, cytoplasmic vacuolation and cell death induced by morusin in EOC cells. Moreover, DIDS pretreatment also suppressed morusin-induced accumulation of ER stress markers, ROS production and depletion ofΔψm. Consistently, tumor xenograft assays showed that co-treatment with DIDS partially reversed the inhibitory effects of morusin on tumor growth in vivo and inhibited the increased levels of ER stress markers induced by morusin in tumor tissues. Collectively, our results suggest that VDAC-mediated Cainflux into mitochondria and subsequent mitochondrial Caoverload contribute to mitochondrial swelling and dysfunction, leading to morusin-induced paraptosis-like cell death in EOC. This study may provide alternative therapeutic strategies for EOC exhibiting resistance to apoptosis.

Study Type : In Vitro Study

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