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.
Highlights
Death-associated protein kinase-1 (DAPK1) is a Ca2+ /calmodulin (CaM)-regulated serine/threonine kinase that mediates cell death [1]
We investigated whether treating chemoresistant ovarian cancer cells with gliotoxin prevents cell growth and induces apoptosis
Cells treated with gliotoxin followed by paclitaxel had increased expression of DAPK1 and transcriptionally active p63 (TAp63), a p53 family member (Figure 3B)
Summary
Death-associated protein kinase-1 (DAPK1) is a Ca2+ /calmodulin (CaM)-regulated serine/threonine kinase that mediates cell death [1]. Overexpression or activation of DAPK1, as a tumor suppressor, is involved in cell death. Ectopic DAPK expression induces p53-dependent apoptosis in mouse embryo fibroblasts [5], and tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) induce DAPK1 expression through inhibiting NF-κB activity [6]. DAPK1 activation requires cell cycle arrest and caspase-dependent apoptosis [7] and contributes to autophagic cell death by reducing the interaction between Beclin-1 and Bcl-2 and Bcl-XL [8]. DAPK-1 induces caspase-independent cell death through activating autophagosome formation [9]. DAPK1 sometimes antagonizes apoptosis in a cell-type-dependent manner. DAPK1 depletion using antisense DAPK1 cDNA promotes caspase-mediated apoptosis via TNF [10], and DAPK1 plays an essential role in the proliferation of
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