DKK1 is a potential novel mediator of cisplatin-refractoriness in non-small cell lung cancer cell lines.
BACKGROUND
Platinum compounds are the mainstay of chemotherapy for lung cancer. Unfortunately treatment failure remains a critical issue since about 60% of all non-small cell lung cancer (NSCLC) patients display intrinsic platinum resistance.


METHODS
We analyzed global gene expression profiles of NSCLC clones surviving a pulse treatment with cisplatin and mapped deregulated signaling networks in silico by Ingenuity Pathway Analysis (IPA). Further validation was done using siRNA.


RESULTS
The pooled cisplatin-surviving NSCLC clones from each of the biological replicates demonstrated heterogeneous gene expression patterns both in terms of the number and the identity of the altered genes. Genes involved in Wnt signaling pathway (Dickkopf-1, DKK1), DNA repair machinery (XRCC2) and cell-cell/cell-matrix interaction (FMN1, LGALS9) were among the top deregulated genes by microarray in these replicates and were validated by q-RT-PCR. We focused on DKK1 which previously was reported to be overexpressed in NSCLC patients. IPA network analysis revealed coordinate up-regulation of several DKK1 transcriptional regulators (TCF4, EZH2, DNAJB6 and HDAC2) in cisplatin-surviving clones from that biological replicate. Knockdown of DKK1 by siRNA sensitized for cisplatin in two different NSCLC cell lines and in ovarian A2780 cells, but not in the A2780 cis subline made resistant to cisplatin by chronic exposure, suggesting a role of DKK1 in intrinsic but not acquired platinum refractoriness.


CONCLUSIONS
We identified DKK1 as a possible marker of a cisplatin-refractory phenotype and as a potential novel therapeutic target to improve platinum response of NSCLC cells.
Karolinska Biomics Center, Department of Oncology-Pathology, Karolinska Institutet, SE-171 76, Stockholm, Sweden. Hogir.Salim@ki.se.
Hogir
H
Salim
Karolinska Biomics Center, Department of Oncology-Pathology, Karolinska Institutet, SE-171 76, Stockholm, Sweden. Dali.Zong@nih.gov.
Dali
D
Zong
Karolinska Biomics Center, Department of Oncology-Pathology, Karolinska Institutet, SE-171 76, Stockholm, Sweden. Petra.Haag@ki.se.
Petra
P
Hååg
Karolinska Biomics Center, Department of Oncology-Pathology, Karolinska Institutet, SE-171 76, Stockholm, Sweden. Metka.Novak@ki.se.
Metka
M
Novak
Karolinska Biomics Center, Department of Oncology-Pathology, Karolinska Institutet, SE-171 76, Stockholm, Sweden. Birgitta.Mork@ki.se.
Birgitta
B
Mörk
Karolinska Biomics Center, Department of Oncology-Pathology, Karolinska Institutet, SE-171 76, Stockholm, Sweden. Rolf.Lewensohn@ki.se.
Rolf
R
Lewensohn
Karolinska Biomics Center, Department of Oncology-Pathology, Karolinska Institutet, SE-171 76, Stockholm, Sweden. Lovisa.Lundholm@su.se.
Lovisa
L
Lundholm
Karolinska Biomics Center, Department of Oncology-Pathology, Karolinska Institutet, SE-171 76, Stockholm, Sweden. Kristina.Viktorsson@ki.se.
Kristina
K
Viktorsson
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use*; D002999:Clone Cells; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D015151:Immunoblotting; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction
D000970:Antineoplastic Agents; C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D002945:Cisplatin