Quantitative Targeted Proteomics of Pancreatic Cancer: Deoxycytidine Kinase Protein Level Correlates to Progression-Free Survival of Patients Receiving Gemcitabine Treatment.
The purpose of the present study is to identify the determinant(s) of gemcitabine (dFdC)-sensitivity in pancreatic cancer tissues of patients treated with dFdC alone and in pancreatic cancer cell lines exposed to dFdC in vitro. Protein expression levels of 12 enzymes and 13 transporters potentially involved in transport and metabolism of dFdC in pancreatic cancer cell lines and tissues were quantified by means of our LC-MS/MS-based quantitative targeted proteomics technology. Protein expression levels of deoxycytidine kinase (dCK), uridine monophosphate-cytidine monophosphate (UMP-CMP) kinase, cytosolic nucleotidase III (cN-III), and equilibrative nucleoside transporter 1 (ENT1) were significantly correlated with IC50 or 1/IC50 in five cell lines with different sensitivities to dFdC (p < 0.05). Expression levels of the selected proteins in pancreatic cancer tissues of 10 patients with different progression-free survival (PFS) (49-955 days) were quantified, and their relationship with PFS was examined. Only the protein expression level of dCK was significantly correlated with PFS (p < 0.05). Multiple regression analysis was also performed, and combinations of ENT1, UMP-CMP kinase, CTPS1, and dCK were highly correlated with PFS. Our results indicate that the protein expression level of dCK in pancreatic cancer tissue is a good predictor of PFS, and thus dCK may be the best biomarker of dFdC sensitivity in pancreatic cancer patients treated with dFdC, although other proteins would also contribute to dFdC-sensitivity at the cellular level in vivo and in vitro.
Membrane Transport and Drug Targeting Laboratory, Tohoku University Graduate School of Pharmaceutical Sciences , Sendai, Japan.
Ken
K
Ohmine
Division of Hepato-Biliary-Pancreatic Surgery, Tohoku University Graduate School of Medicine , Sendai, Japan.
Kei
K
Kawaguchi
Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University , Kumamoto, Japan.
Sumio
S
Ohtsuki
Division of Hepato-Biliary-Pancreatic Surgery, Tohoku University Graduate School of Medicine , Sendai, Japan.
Fuyuhiko
F
Motoi
Division of Hepato-Biliary-Pancreatic Surgery, Tohoku University Graduate School of Medicine , Sendai, Japan.
Hideo
H
Ohtsuka
Laboratory of Veterinary Pathology, Azabu University School of Veterinary Medicine , Sagamihara, Japan.
Junichi
J
Kamiie
Department of Clinical Biology and Hormonal Regulation, Tohoku University Graduate School of Medicine , Sendai, Japan.
Takaaki
T
Abe
Division of Hepato-Biliary-Pancreatic Surgery, Tohoku University Graduate School of Medicine , Sendai, Japan.
Michiaki
M
Unno
Membrane Transport and Drug Targeting Laboratory, Tohoku University Graduate School of Pharmaceutical Sciences , Sendai, Japan.
Tetsuya
T
Terasaki
D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D003842:Deoxycytidine Kinase / Q000378:metabolism*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality*; D040901:Proteomics / Q000379:methods*; D015996:Survival Rate; D053719:Tandem Mass Spectrometry; D014407:Tumor Cells, Cultured; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D003842:Deoxycytidine Kinase; D000093542:Gemcitabine
deoxycytidine kinase; drug resistance; gemcitabine; pancreatic cancer; targeted proteomics