Pardaxin Activates Excessive Mitophagy and Mitochondria-Mediated Apoptosis in Human Ovarian Cancer by Inducing Reactive Oxygen Species

被引：28

作者：

Chen, Yen-Po ^{[1
,2
]}

Shih, Po-Chang ^{[1
,3
]}

Feng, Chien-Wei ^{[4
]}

Wu, Chang-Cheng ^{[1
,5
]}

Tsui, Kuan-Hao ^{[6
,7
]}

Lin, You-Hsien ^{[8
,9
]}

Kuo, Hsiao-Mei ^{[1
,10
]}

Wen, Zhi-Hong ^{[1
,11
]}

机构：

[1] Natl Sun Yat Sen Univ, Dept Marine Biotechnol & Resources, Kaohsiung 80424, Taiwan

[2] Kaohsiung Armed Forces Gen Hosp, Dept Obstet & Gynecol, Kaohsiung 80284, Taiwan

[3] Kaohsiung Chang Gung Mem Hosp, Dept Neurosurg, Kaohsiung 83301, Taiwan

[4] Kaohsiung Med Univ, Kaohsiung Med Univ Hosp, Dept Obstet & Gynecol, Kaohsiung 80756, Taiwan

[5] Kaohsiung Armed Forces Gen Hosp, Dept Obstet & Gynecol, Zouying Branch, Kaohsiung 81342, Taiwan

[6] Kaohsiung Vet Gen Hosp, Dept Obstet & Gynecol, Kaohsiung 81341, Taiwan

[7] Natl Yang Ming Univ, Inst Clin Med, Dept Obstet & Gynecol, Taipei 11221, Taiwan

[8] Kaohsiung Municipal Tatung Hosp, Dept Internal Med, Kaohsiung 80145, Taiwan

[9] Kaohsiung Med Univ, Dept Med, Coll Med, Kaohsiung 80708, Taiwan

[10] Natl Sun Yat Sen Univ, Ctr Neurosci, Kaohsiung 80424, Taiwan

[11] Natl Sun Yat Sen Univ, Inst Med Sci & Technol, Kaohsiung 80424, Taiwan

来源：

ANTIOXIDANTS | 2021年 / 10卷 / 12期

关键词：

pardaxin; mitophagy; mitochondria; reactive oxygen species; apoptosis; natural product; ovarian cancer; oxidative phosphorylation; autophagosome; mitochondrial membrane potential; SIGNALING PATHWAYS; AUTOPHAGY; DYNAMICS; DYSFUNCTION; FISSION; STRESS; FUSION; DRUGS; CELLS; ROS;

D O I：

10.3390/antiox10121883

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Most ovarian cancer (OC) patients are diagnosed with stage III or higher disease, resulting in a poor prognosis. Currently, paclitaxel combined with carboplatin shows the best treatment outcome for OC. However, no effective drug is available for patients that do not respond to treatment; thus, new drugs for OC are needed. We evaluated the antimicrobial peptide, pardaxin, in PA-1 and SKOV3 cells. Pardaxin induced apoptosis as determined by MTT and TUNEL assays, as well as activation of caspases-9/3, Bid, t-Bid, and Bax, whereas Bcl-2 was downregulated. The IC50 values for pardaxin were 4.6-3.0 mu M at 24 and 48 h. Mitochondrial and intracellular reactive oxygen species (ROS) were overproduced and associated with disrupted mitochondrial membrane potential and respiratory capacity. Additionally, the mitochondrial network was fragmented with downregulated fusogenic proteins, MFN1/2 and L-/S-OPA1, and upregulated fission-related proteins, DRP1 and FIS1. Autophagy was also activated as evidenced by increased expression of autophagosome formation-related proteins, Beclin, p62, and LC3. Enhanced mitochondrial fragmentation and autophagy indicate that mitophagy was activated. ROS-induced cytotoxicity was reversed by the addition of N-acetylcysteine, confirming ROS overproduction as a contributor. Taken together, pardaxin demonstrated promising anticancer activity in OC cells, which warrants further preclinical development of this compound.

引用

页数：22