Molecule Information

General Information of the Molecule (ID: Mol01902)

• Name: Pyruvate dehydrogenase kinase 2 (PDK2) ,Homo sapiens
• Synonyms: PDK2; PDHK2
• Molecule Type: Protein
• Gene Name: PDK2
• Gene ID: 5164
• Location: chr17:50,094,737-50,112,152[+]
• Sequence:
  MRWVWALLKNASLAGAPKYIEHFSKFSPSPLSMKQFLDFGSSNACEKTSFTFLRQELPVR
  LANIMKEINLLPDRVLSTPSVQLVQSWYVQSLLDIMEFLDKDPEDHRTLSQFTDALVTIR
  NRHNDVVPTMAQGVLEYKDTYGDDPVSNQNIQYFLDRFYLSRISIRMLINQHTLIFDGST
  NPAHPKHIGSIDPNCNVSEVVKDAYDMAKLLCDKYYMASPDLEIQEINAANSKQPIHMVY
  VPSHLYHMLFELFKNAMRATVESHESSLILPPIKVMVALGEEDLSIKMSDRGGGVPLRKI
  ERLFSYMYSTAPTPQPGTGGTPLAGFGYGLPISRLYAKYFQGDLQLFSMEGFGTDAVIYL
  KALSTDSVERLPVYNKSAWRHYQTIQEAGDWCVPSTEPKNTSTYRVS
• 3D-structure: PDB ID: 6LIO; Classification: Transferase; Method: X-ray diffraction; Resolution: 1.76 Å
• Function: Kinase that plays a key role in the regulation of glucose and fatty acid metabolism and homeostasis via phosphorylation of the pyruvate dehydrogenase subunits PDHA1 and PDHA2. This inhibits pyruvate dehydrogenase activity, and thereby regulates metabolite flux through the tricarboxylic acid cycle, down-regulates aerobic respiration and inhibits the formation of acetyl-coenzyme A from pyruvate. Inhibition of pyruvate dehydrogenase decreases glucose utilization and increases fat metabolism. Mediates cellular responses to insulin. Plays an important role in maintaining normal blood glucose levels and in metabolic adaptation to nutrient availability. Via its regulation of pyruvate dehydrogenase activity, plays an important role in maintaining normal blood pH and in preventing the accumulation of ketone bodies under starvation. Plays a role in the regulation of cell proliferation and in resistance to apoptosis under oxidative stress. Plays a role in p53/TP53-mediated apoptosis.
• Uniprot ID: PDK2_HUMAN
• Ensembl ID: ENSG00000005882
• HGNC ID: HGNC:8810

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

Type(s) of Resistant Mechanism of This Molecule

  MRAP: Metabolic Reprogramming via Altered Pathways

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 2 drug(s) in total

Cisplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Head and neck cancer [ICD-11: 2D42.0] [1]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Head and neck cancer [ICD-11: 2D42.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HNC SAS cells; Head and Neck; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: After PDK1 and PDK2 knockdown, we discovered increased ATP production and decreased lactate production in TGFbeta1-treated and untreated HNC cells. However, only PDK2 silencing significantly inhibited the clonogenic ability of HNC cells. We subsequently found that TGFbeta1-promoted migration and invasion capabilities were decreased in PDK1 and PDK2 knockdown cells. The tumor spheroid-forming capability, motility, CSC genes, and multidrug-resistant genes were downregulated in PDK1 and PDK2 silencing CSCs. PDK1 and PDK2 inhibition reversed cisplatin and gemcitabine resistance of CSCs, but not paclitaxel resistance.

Disease Class: Esophageal squamous cell carcinoma [ICD-11: 2B70.3] [2]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Male BALB/c nude mice (6-week old), with KYSE150 cells; Mice
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: PDK1 inhibition by siRNA or DCA significantly suppressed the growth of ESCC cells. miR-6516-5p/PDK1 axis suppressed the growth of ESCC cell by inhibiting glycolysis. Moreover, DCA and DDP synergistically inhibited the progression and glycolysis ability of ESCC cells both in vitro and in vivo by increasing oxidative stress partly through the suppression of Keap1/Nrf2 signaling pathway.

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Ovarian clear cell Carcinoma [ICD-11: 2C73.1] [3]

• Resistant Disease: Ovarian clear cell Carcinoma [ICD-11: 2C73.1]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: RMG5 cells; Skin; Homo sapiens (Human); N.A.
• In Vitro Model: RMG1 cells; Ovary; Homo sapiens (Human); CVCL_1662
• In Vivo Model: ICR/nu female mice model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR; Western blotting assay
• Experiment for Drug Resistance: WST-8 assay
• Mechanism Description: Patients with high expression of pyruvate dehydrogenase kinase 2 (PDK2) had a worse prognosis than those with low PDK2 expression. Furthermore, inhibition of PDK2 synergistically enhanced cisplatin sensitivity by activating the electron transport chain and by increasing the production of mitochondrial reactive oxygen species.

Gemcitabine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Head and neck cancer [ICD-11: 2D42.0] [1]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Head and neck cancer [ICD-11: 2D42.0]
• Resistant Drug: Gemcitabine
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HNC SAS cells; Head and Neck; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: After PDK1 and PDK2 knockdown, we discovered increased ATP production and decreased lactate production in TGFbeta1-treated and untreated HNC cells. However, only PDK2 silencing significantly inhibited the clonogenic ability of HNC cells. We subsequently found that TGFbeta1-promoted migration and invasion capabilities were decreased in PDK1 and PDK2 knockdown cells. The tumor spheroid-forming capability, motility, CSC genes, and multidrug-resistant genes were downregulated in PDK1 and PDK2 silencing CSCs. PDK1 and PDK2 inhibition reversed cisplatin and gemcitabine resistance of CSCs, but not paclitaxel resistance.

Clinical Trial Drug(s) 1 drug(s) in total

Dichloroacetic acid

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Esophageal squamous cell carcinoma [ICD-11: 2B70.3] [2]

• Metabolic Type: Glucose metabolism
• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Sensitive Drug: Dichloroacetic acid
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Male BALB/c nude mice (6-week old), with KYSE150 cells; Mice
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: PDK1 inhibition by siRNA or DCA significantly suppressed the growth of ESCC cells. miR-6516-5p/PDK1 axis suppressed the growth of ESCC cell by inhibiting glycolysis. Moreover, DCA and DDP synergistically inhibited the progression and glycolysis ability of ESCC cells both in vitro and in vivo by increasing oxidative stress partly through the suppression of Keap1/Nrf2 signaling pathway.

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Ovarian cancer [ICD-11: 2C73]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Ovary
• The Specified Disease: Ovarian cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.93E-02; Fold-change: -1.63E-01; Z-score: -4.38E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 2.14E-02; Fold-change: 1.60E-01; Z-score: 5.08E-01

References

• Ref 1: PDK1- and PDK2-mediated metabolic reprogramming contributes to the TGFbeta1-promoted stem-like properties in head and neck cancer. Cancer Metab. 2022 Dec 6;10(1):23.
• Ref 2: PDK1 regulates the progression of esophageal squamous cell carcinoma through metabolic reprogramming. Mol Carcinog. 2023 Jun;62(6):866-881.
• Ref 3: PDK2 leads to cisplatin resistance through suppression of mitochondrial function in ovarian clear cell carcinoma .Cancer Sci. 2021 Nov;112(11):4627-4640. doi: 10.1111/cas.15125. Epub 2021 Sep 13. 10.1111/cas.15125