Dickkopf-3 (Dkk3) induces apoptosis in cisplatin-resistant lung adenocarcinoma cells via the Wnt/β-catenin pathway

Abstract

Abstract. Previous studies have shown that is inactivated in lung cancer cells, while the inactivation of the Wnt/β-catenin signaling pathway by Dkk3 inhibits lung cancer progression. In the present study, we investigated whether Dkk3 enhances the sensitivity of lung cancer cells to cisplatin. A549, Calu1 and H460 lung adenocarcinoma cell lines were transfected with DKK3 siRNA, while the cisplatin-resistant subline A549cis was transfected with DKK3. DKK3 expression was attenuated in A549cis, Calu1cis and H460cis compared to A549, Calu1 and H460, respectively. Lung adenocarcinoma cell growth, proliferation, apoptosis, cell cycle in vitro and in vivo were then analyzed. DKK3 knockdown by siRNA transfection rendered A549, Calu1 and H460 resistant to cisplatin. As a result of DKK3 transfection, the expression of DKK3 and E-cadherin was significantly upregulated, while that of MMP7, survivin, c-myc and cyclin D1 was downregulated. DKK3 overexpression retarded cell proliferation, induced cell cycle arrest and apoptosis, and reduced cell invasive ability in the A549 and A549cis cells. In addition, the proportions of apoptotic cells and the PARP level were significantly increased in A549cis-and H460cis-DKK3 cells treated with cisplatin. Moreover, tumor growth was retarded more in cisplatin-treated nude mice seeded with A549cis-DKK3 cells than with A549cis cells. Cell viability increased with the pretreatment of SB216763 for 2 h in A549cis and A549cis-DKK3 cells incubated with cisplatin (1 µM) for 72 h. In conclusion, the re-activation of Dkk3 enhances the chemosensitivity to cisplatin in cisplatin-resistant lung adenocarcinoma cell lines, which requires additional studies to realize this potential in clinical use. IntroductionLung cancer has emerged as the third leading cause of cancer-related mortality worldwide (1). In the USA, over 200,000 new lung cancer cases are diagnosed annually, causing over 150,000 deaths in one year (1). Approximately 85% of lung cancer patients suffer from non-small cell lung cancer (NSCLC). Due to the comparative therapeutic advantage, cisplatin-based combination regimens are recommended as the optimal choice currently for the majority of NSCLC patients indicative of chemotherapy or adjuvant chemotherapy (2). However, the average survival time for patients with advanced stage of NSCLC receiving cisplatin plus gemcitabine treatment is ~16 months and may even be reduced to 12 months in those with cisplatin-resistance (3). The dilemma in managing late-stage NSCLC requires the elucidation of the mechanisms in cisplatin resistance to define novel, effective and applicable therapeutic targets for lung cancer (2,3).Several signal transduction pathways controlling chemosensitivity are aberrantly activated in various types of cancer, among which Wnt is of special significance (4). The role of Wnt1/Int-1 in the induction of mouse mammary tumor as an integration site for mouse mammary tumor virus (MMTV) was first recognized 30 years ago (4). Wnt/β-catenin signaling is initiated by the binding of secre...

Wnt activation protects against neomycin-induced hair cell damage in the mouse cochlea

“…Previous studies reported that several pathways are involved in β -catenin deficiency-induced cell death, including increased apoptosis of hepatic progenitor cells due to enhanced expression of cleaved caspase-9 and caspase-3 when β -catenin expression is blocked, 16 increased apoptosis in cisplatin-resistant lung adenocarcinoma cells when DKK3 is used to inhibit the Wnt/ β -catenin pathway, 35 and increased si-LGR5-induced apoptosis when the mitochondrial membrane potential is disrupted in colorectal cancer cells. 36 In our study, significantly greater HC loss was observed in β -catenin knockout cochleae compared with controls after neomycin treatment ( Figure 2 ), which was accompanied by upregulation of the pro-apoptotic transcription factor Foxo3 and its downstream target gene Bim ( Figure 8 ).…”

Curcumin reduces mitomycin C resistance in breast cancer stem cells by regulating Bcl-2 family-mediated apoptosis

“…The results suggested that curcumin increases MMC-mediated cell death in BCSCs by regulating Bcl-2 family protein expression via the mitochondria-dependent pathway. Furthermore, curcumin-treated BCSCs exhibited the typical features of apoptotic cell death, including shrinkage, transient phosphatidylserine exposure, increased membrane permeability, and a decrease in mitochondrial membrane potential [ 44 ]. In this study, the combination treatment of curcumin and MMC also reduced mitochondrial membrane potential in MCF-7 BCSCs by approximately 20% compared with the treatment with curcumin or MMC separately (Fig.…”

Dickkopf-3 is upregulated in osteoarthritis and has a chondroprotective role

“…Dkk3 activates or inhibits Wnt signaling in a tissue-dependent manner and its impact on cartilage Wnt signaling is unknown 7 , 8 , 9 . Dkk3 is a tumour suppressor that inhibits proliferation of cancer cells and is downregulated in several types of human cancer 8 , 9 , 10 . It can modulate inflammatory cell activity, maintain tissue organisation via TGFβ signaling and can protect against myocardial infarction-induced fibrosis 11 , 12 , 13 , 14 .…”