title: Dickkopf-3 (Dkk3) induces apoptosis in cisplatin-resistant lung adenocarcinoma cells via the Wnt/β-catenin pathway.
abstract: Previous studies have shown that Dickkopf‑3 (Dkk3) 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.
authors.affiliation: Department of Respiratory Medicine, The People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Respiratory Medicine, The People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China.
authors.forename: Li-Jun
authors.initials: LJ
authors.lastname: Ma
authors.affiliation: Department of Infectious Disease, The People's Hospital of Zhengzhou University, Zhengzhou, Henan 450000, P.R. China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Kang
authors.affiliation: Department of Respiratory Medicine, The People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Respiratory Medicine, The People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China.
authors.forename: Xiao-Ju
authors.initials: XJ
authors.lastname: Zhang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D018925:Chemokines; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D060449:Wnt Signaling Pathway
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D018925:Chemokines; C498624:DKK3 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D002945:Cisplatin