Proteins and single nucleotide polymorphisms involved in apoptosis, growth control, and DNA repair predict cisplatin sensitivity in head and neck cancer cell lines.
The present study was undertaken to evaluate the possibility of using a panel of proteins and single nucleotide polymorphisms (SNPs) involved in apoptosis, growth control, and DNA repair as predictive markers for cisplatin sensitivity. For this purpose the intrinsic cisplatin sensitivity (ICS) was determined in 39 cell lines derived from squamous cell carcinomas of the head and neck using a colony-forming assay. In these cell lines and in normal oral keratinocytes (NOK), the expression of epidermal growth factor receptor (EGFR), Hsp70, Bax, Bcl-2, Bcl-XL, survivin, and COX-2 was determined. Moreover, the p53, MDM2, FGFR4, XPC, XPD, XRCC1, and XRCC3 genes were analyzed for the presence of specific single nucleotide polymorphisms (SNPs). Pearson's correlation test showed that EGFR was the only protein that was significantly correlated to the ICS (r=0.388, p=0.015). The combination of EGFR, Hsp70, Bax, and Bcl-2 gave the strongest correlation (r=0.566, p<or=0.001), whereas Bax alone had the second highest influence on the ICS. Furthermore, all four SNPs within genes involved in DNA repair, i.e. XPC, XPD, XRCC1, and XRCC3, tended to influence the ICS. In order to find the combination of factors, on both protein and gene levels, with the highest correlation to ICS, a multivariate statistical calculation was performed. Our results indicate that SNPs in DNA repair genes (XRCC3241 and XPD751) influence the ICS and together with the expression of EGFR, Hsp70, Bax, and Bcl-2, they could predict the cisplatin sensitivity of head and neck cancer cell lines (r=0.614, p<or=0.001).
Farnebo
Lovisa
L
Division of Otorhinolaryngology, Linköping University Hospital, Linköping, Sweden.
Jedlinski
Adam
A
Ansell
Anna
A
Vainikka
Linda
L
Thunell
Lena K
LK
Grénman
Reidar
R
Johansson
Ann-Charlotte
AC
Roberg
Karin
K
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002945:Cisplatin / Q000627:therapeutic use*; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D000076105:X-ray Repair Cross Complementing Protein 1; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000235:genetics
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D000076105:X-ray Repair Cross Complementing Protein 1; C110901:X-ray repair cross complementing protein 3; C000619371:XRCC1 protein, human; D051028:bcl-2-Associated X Protein; C086984:XPC protein, human; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C496371:FGFR4 protein, human; D051499:Receptor, Fibroblast Growth Factor, Type 4; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human; D002945:Cisplatin