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...