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Gliotoxin Enhances Autophagic Cell Death via the DAPK1-TAp63 Signaling Pathway in Paclitaxel-Resistant Ovarian Cancer Cells

1
Department of Biochemistry, Kosin University College of Medicine, Busan 49267, Korea
2
Department of Anatomy, Inje University College of Medicine, Busan 47392, Korea
*
Authors to whom correspondence should be addressed.
Mar. Drugs 2019, 17(7), 412; https://doi.org/10.3390/md17070412
Received: 24 June 2019 / Revised: 10 July 2019 / Accepted: 10 July 2019 / Published: 12 July 2019
(This article belongs to the Special Issue Selected Papers from the 3rd International Symposium on Life Science)
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Abstract

Death-associated protein kinase 1 (DAPK1) expression induced by diverse death stimuli mediates apoptotic activity in various cancers, including ovarian cancer. In addition, mutual interaction between the tumor suppressor p53 and DAPK1 influences survival and death in several cancer cell lines. However, the exact role and connection of DAPK1 and p53 family proteins (p53, p63, and p73) in drug-resistant ovarian cancer cells have not been studied previously. In this study, we investigated whether DAPK1 induction by gliotoxin derived from marine fungus regulates the level of transcriptionally active p63 (TAp63) to promote apoptosis in an autophagy-dependent manner. Pre-exposure of paclitaxel-resistant ovarian cancer cells to gliotoxin inhibited the expression of multidrug resistant-associated proteins (MDR1 and MRP1-3), disrupted the mitochondrial membrane potential, and induced caspase-dependent apoptosis through autophagy induction after subsequent treatment with paclitaxel. Gene silencing of DAPK1 prevented TAp63-mediated downregulation of MDR1 and MRP1-3 and autophagic cell death after sequential treatment with gliotoxin and then paclitaxel. However, pretreatment with 3-methyladenine (3-MA), an autophagy inhibitor, had no effect on the levels of DAPK1 and TAp63 or on the inhibition of MDR1 and MRP1-3. These results suggest that DAPK1-mediated TAp63 upregulation is one of the critical pathways that induce apoptosis in chemoresistant cancer cells. View Full-Text
Keywords: gliotoxin; DAPK1; TAp63; autophagy; drug resistance; ovarian cancer gliotoxin; DAPK1; TAp63; autophagy; drug resistance; ovarian cancer
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Park, G.-B.; Jeong, J.-Y.; Kim, D. Gliotoxin Enhances Autophagic Cell Death via the DAPK1-TAp63 Signaling Pathway in Paclitaxel-Resistant Ovarian Cancer Cells. Mar. Drugs 2019, 17, 412.

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