Molecule Information

General Information of the Molecule (ID: Mol00317)

• Name: Deoxycytidine kinase (DCK) ,Homo sapiens
• Synonyms: dCK; Deoxyadenosine kinase; Deoxyguanosine kinase
• Molecule Type: Protein
• Gene Name: DCK
• Gene ID: 1633
• Location: chr4:70992538-71030914[+]
• Sequence:
  MATPPKRSCPSFSASSEGTRIKKISIEGNIAAGKSTFVNILKQLCEDWEVVPEPVARWCN
  VQSTQDEFEELTMSQKNGGNVLQMMYEKPERWSFTFQTYACLSRIRAQLASLNGKLKDAE
  KPVLFFERSVYSDRYIFASNLYESECMNETEWTIYQDWHDWMNNQFGQSLELDGIIYLQA
  TPETCLHRIYLRGRNEEQGIPLEYLEKLHYKHESWLLHRTLKTNFDYLQEVPILTLDVNE
  DFKDKYESLVEKVKEFLSTL
• Function: Phosphorylates the deoxyribonucleosides deoxycytidine, deoxyguanosine and deoxyadenosine. Has broad substrate specificity, and does not display selectivity based on the chirality of the substrate. It is also an essential enzyme for the phosphorylation of numerous nucleoside analogs widely employed as antiviral and chemotherapeutic agents.
• Uniprot ID: DCK_HUMAN
• Ensembl ID: ENSG00000156136
• HGNC ID: HGNC:2704

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  DISM: Drug Inactivation by Structure Modification

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 3 drug(s) in total

Cladribine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Disease Class: Acute lymphocytic leukemia [1]

• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Resistant Drug: Cladribine
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Staphylococcus aureus strain; 1280
• Mechanism Description: Cladribine cannot be deaminated by adenosine deaminase(ADA) and is phosphorylated to cladribine-MP by dCK. Cladribine self potentiates its own activation by activation of dCK. The cytotoxicity mainly depends on the accumulation of cladribine-TP after phosphoryl-ation of cladribine-MP by nucleoside MP kinase and nucleoside diphosphate kinase in the cells. Down regulation of all activating enzymes such as dCK or dGK due to loss of expression or through mutation, has been shown to cause resistance to cladribine. However, the most frequently described form of acquired resistance to cladribine in vitro is dCK de ciency and reduction in dCK activity is probably the major determinant of cladribine resistance.

Cytarabine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Disease Class: Acute lymphocytic leukemia [2]

• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Resistant Drug: Cytarabine
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Jurkat cells; Pleural effusion; Homo sapiens (Human); CVCL_0065
• In Vitro Model: Nalm-6 cells; Peripheral blood; Homo sapiens (Human); CVCL_0092
• Experiment for Molecule Alteration: Real-time quantitative PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Low-concentration cytarabine (Ara-C) continuously induced and cultured Jurkat and Nalm-6 cells to construct cytarabine-resistant cell lines Jurkat/Ara-C and Nalm-6/Ara-C. The results of real-time quantitative PCR showed that the expression of deoxycytidine kinase (DCk) and cytidine deaminase (CDA) were significantly down-regulated in drug-resistant cells (P<0.05).

Disease Class: Leukemia [3]

• Resistant Disease: Leukemia [ICD-11: 2B33.6]
• Resistant Drug: Cytarabine
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Deoxycitidine kinase plays a pivotal role since phosphorylation of cytarabine preserves intracellular retention of the drug and prevents from inactivation to its uridine derivative, uracil arabinoside, by cytidine deaminase. The intracellular accumulation of cytarabine triphosphate, the active cytotoxic metabolite, is proportional to the cellular DCk level which has led to the conclusion that DCk enzyme retains a rate-limiting role for the activation of cytarabine.

Disease Class: Lymphoma [3]

• Resistant Disease: Lymphoma [ICD-11: 2A90- 2A85]
• Resistant Drug: Cytarabine
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Deoxycitidine kinase plays a pivotal role since phosphorylation of cytarabine preserves intracellular retention of the drug and prevents from inactivation to its uridine derivative, uracil arabinoside, by cytidine deaminase. The intracellular accumulation of cytarabine triphosphate, the active cytotoxic metabolite, is proportional to the cellular DCk level which has led to the conclusion that DCk enzyme retains a rate-limiting role for the activation of cytarabine.

Gemcitabine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Disease Class: Pancreatic ductal adenocarcinoma [4]

• Resistant Disease: Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0]
• Resistant Drug: Gemcitabine
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Once taken up into the cell, gemcitabine is phosphorylated by deoxycytidine kinase (dCK) to produce dFdCMP. In turn, dFdCMP is converted by other pyrimidine kinases to its active diphosphate and triphosphate derivatives, dFdCDP and dFdCTP. Due to the central role of dCK in gemcitabine metabolism, its deficiency is a major contributor to gemcitabine resistance.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Colon cancer [5]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Sensitive Drug: Gemcitabine
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: Colo320 cells; Colon; Homo sapiens (Human); CVCL_1989
• In Vitro Model: WiDR cells; Colon; Homo sapiens (Human); CVCL_2760
• Experiment for Molecule Alteration: qRT -PCR
• Experiment for Drug Resistance: Sulforhodamide B (SRB) test assay
• Mechanism Description: Deoxycytidine kinase (dCk) is essential for phosphorylation of natural deoxynucleosides andanalogs, such as gemcitabine and cytarabine, two widely used anticancer compounds. miR-330 expression negatively correlated withdCk mRNA expression, suggesting a role of miR-330 in post-transcriptional regulationof dCk. Expression of miR-330 in various colon and lung cancer cell lines,as measured by QRT-PCR, varied five-fold between samples and correlated with in-vitro gemcitabineresistance.

Disease Class: Lung cancer [5]

• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Sensitive Drug: Gemcitabine
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: SW1573 cells; Lung; Homo sapiens (Human); CVCL_1720
• Experiment for Molecule Alteration: qRT -PCR
• Experiment for Drug Resistance: Sulforhodamide B (SRB) test assay
• Mechanism Description: Deoxycytidine kinase (dCk) is essential for phosphorylation of natural deoxynucleosides andanalogs, such as gemcitabine and cytarabine, two widely used anticancer compounds. miR-330 expression negatively correlated withdCk mRNA expression, suggesting a role of miR-330 in post-transcriptional regulationof dCk. Expression of miR-330 in various colon and lung cancer cell lines,as measured by QRT-PCR, varied five-fold between samples and correlated with in-vitro gemcitabineresistance.

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Lymphoma [ICD-11: 2A90- 2A85]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Tonsil tissue
• The Specified Disease: Lymphoma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 4.39E-01; Fold-change: 2.33E-01; Z-score: 3.09E-01

Colon cancer [ICD-11: 2B90]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Colon
• The Specified Disease: Colon cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.10E-05; Fold-change: 2.01E-01; Z-score: 4.47E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 1.34E-01; Fold-change: 1.40E-01; Z-score: 2.14E-01

Pancreatic cancer [ICD-11: 2C10]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Pancreas
• The Specified Disease: Pancreatic cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 5.40E-02; Fold-change: 6.67E-01; Z-score: 5.94E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 1.40E-02; Fold-change: 6.58E-01; Z-score: 6.18E-01

Lung cancer [ICD-11: 2C25]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Lung
• The Specified Disease: Lung cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.56E-05; Fold-change: 8.91E-02; Z-score: 1.55E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 2.35E-22; Fold-change: 4.71E-01; Z-score: 1.04E+00

References

• Ref 1: Pharmacological basis for cladribine resistance .Leuk Lymphoma. 2003 Oct;44(10):1705-12. doi: 10.1080/1042819031000099698. 10.1080/1042819031000099698
• Ref 2: [Establishment of Cytarabine-resistant Acute Lymphoblastic Leukemia Cell Lines and Its Resistance Mechanism]. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2021 Oct;29(5):1403-1410. doi: 10.19746/j.cnki.issn.1009-2137.2021.05.006.
• Ref 3: Response and Toxicity to Cytarabine Therapy in Leukemia and Lymphoma: From Dose Puzzle to Pharmacogenomic Biomarkers. Cancers (Basel). 2021 Feb 25;13(5):966. doi: 10.3390/cancers13050966.
• Ref 4: Gemcitabine resistance in pancreatic ductal adenocarcinoma .Drug Resist Updat. 2015 Nov;23:55-68. doi: 10.1016/j.drup.2015.10.002. Epub 2015 Nov 3. 10.1016/j.drup.2015.10.002
• Ref 5: Regulation of deoxycytidine kinase expression and sensitivity to gemcitabine by micro-RNA 330 and promoter methylation in cancer cells. Nucleosides Nucleotides Nucleic Acids. 2011 Dec;30(12):1214-22. doi: 10.1080/15257770.2011.629271.