Molecule Information

General Information of the Molecule (ID: Mol00105)

• Name: Pyruvate kinase M2 (PKM) ,Homo sapiens
• Synonyms: Cytosolic thyroid hormone-binding protein; CTHBP; Opa-interacting protein 3; OIP-3; Pyruvate kinase 2/3; Pyruvate kinase muscle isozyme; Thyroid hormone-binding protein 1; THBP1; Tumor M2-PK; p58; OIP3; PK2; PK3; PKM2
• Molecule Type: Protein
• Gene Name: PKM
• Gene ID: 5315
• Location: chr15:72199029-72231819[-]
• Sequence:
  MSKPHSEAGTAFIQTQQLHAAMADTFLEHMCRLDIDSPPITARNTGIICTIGPASRSVET
  LKEMIKSGMNVARLNFSHGTHEYHAETIKNVRTATESFASDPILYRPVAVALDTKGPEIR
  TGLIKGSGTAEVELKKGATLKITLDNAYMEKCDENILWLDYKNICKVVEVGSKIYVDDGL
  ISLQVKQKGADFLVTEVENGGSLGSKKGVNLPGAAVDLPAVSEKDIQDLKFGVEQDVDMV
  FASFIRKASDVHEVRKVLGEKGKNIKIISKIENHEGVRRFDEILEASDGIMVARGDLGIE
  IPAEKVFLAQKMMIGRCNRAGKPVICATQMLESMIKKPRPTRAEGSDVANAVLDGADCIM
  LSGETAKGDYPLEAVRMQHLIAREAEAAIYHLQLFEELRRLAPITSDPTEATAVGAVEAS
  FKCCSGAIIVLTKSGRSAHQVARYRPRAPIIAVTRNPQTARQAHLYRGIFPVLCKDPVQE
  AWAEDVDLRVNFAMNVGKARGFFKKGDVVIVLTGWRPGSGFTNTMRVVPVP
• Function: Glycolytic enzyme that catalyzes the transfer of a phosphoryl group from phosphoenolpyruvate (PEP) to ADP, generating ATP. The ratio between the highly active tetrameric form and nearly inactive dimeric form determines whether glucose carbons are channeled to biosynthetic processes or used for glycolytic ATP production. The transition between the 2 forms contributes to the control of glycolysis and is important for tumor cell proliferation and survival. In addition to its role in glycolysis, also regulates transcription. Stimulates POU5F1-mediated transcriptional activation. Promotes in a STAT1-dependent manner, the expression of the immune checkpoint protein CD274 in ARNTL/BMAL1-deficient macrophages. Also acts as a translation regulator for a subset of mRNAs, independently of its pyruvate kinase activity: associates with subpools of endoplasmic reticulum-associated ribosomes, binds directly to the mRNAs translated at the endoplasmic reticulum and promotes translation of these endoplasmic reticulum-destined mRNAs. Plays a general role in caspase independent cell death of tumor cells.
• Uniprot ID: KPYM_HUMAN
• Ensembl ID: ENSG00000067225
• HGNC ID: HGNC:9021

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) 6 drug(s) in total

Sorafenib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Hepatocellular carcinoma [ICD-11: 2C12.2] [1]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Resistant Drug: Sorafenib
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Liver cancer [ICD-11: 2C12]
• The Specified Disease: Liver cancer
• The Studied Tissue: Liver tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.02E-21; Fold-change: 1.99E-01; Z-score: 1.08E+01
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PKM2 mediated glycolysis signaling pathway; Activation; hsa05230
• In Vitro Model: HCCLM3 cells; Liver; Homo sapiens (Human); CVCL_6832
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vivo Model: SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-374b/hnRNPA1/PkM2 axis functions as an important mechanism in sorafenib resistance, with sorafenib-induced miR-374b downregulation and subsequently elevated glycolysis.

Tamoxifen

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast cancer [ICD-11: 2C60.3] [2]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Resistant Drug: Tamoxifen
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Breast cancer [ICD-11: 2C60]
• The Specified Disease: Breast cancer
• The Studied Tissue: Breast tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.62E-40; Fold-change: 1.53E-01; Z-score: 1.50E+01
• Experimental Note: Revealed Based on the Cell Line Data
• Mechanism Description: Hk2, PFkB3, ENO-1, and PkM-2 are the main enzymes of glycolysis and their expression is upregulated in TAMR cells. Hk2 is also involved in the activation of pro-survival autophagy. ENO-1 plays an important role by inhibiting apoptosis via downregulation of c-Myc. In mitochondria, PDk4 phosphorylation regulate Pyruvate dehydrogenase of PDC. NSD2 activates Hk-2, G6PD, and TIGAR expression and upregulates the PPP pathway. PPP produces NADH and Ribulose 5-Phosphate, a substrate for nucleotide biosynthesis. NADH reduces ROS and inhibits apoptosis. LDHA overexpression helps in aerobic glycolysis and indirectly promotes autophagy. To reduce the concentration of lactate in the cells, MCT expression is increased, which facilitates the efflux of lactate and cell survival.

Cisplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Ovarian cancer [ICD-11: 2C73.0] [3]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: COC1 cells; Ovary; Homo sapiens (Human); CVCL_6891
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Down-regulations of PkM2 and HSPD1 involved in MDR in ovarian cancer.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Lung cancer [ICD-11: 2C25.5] [4]

• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Sensitive Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell growth; Activation; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Overexpression of miR133b can inhibit the growth and proliferation of lung cancer stem cells by down regulating PkM2, and can enhance the sensitivity of lung cancer stem cells to DDP.

Doxorubicin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Hepatocellular carcinoma [ICD-11: 2C12.2] [5]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Sensitive Drug: Doxorubicin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: miR122/PKM2 signaling pathway; Regulation; N.A.
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: PLC cells; Liver; Homo sapiens (Human); CVCL_0485
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of miR-122 in Huh7/R cells reversed the doxorubicin-resistance through the inhibition of PkM2, inducing the apoptosis in doxorubicin-resistant cancer cells.

Enzalutamide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Castration-resistant prostate cancer [ICD-11: 2C82.0] [6]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Castration-resistant prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Enzalutamide
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Central carbon metabolism in cancer; Activation; hsa05230
• In Vitro Model: C4-2 cells; Prostate; Homo sapiens (Human); CVCL_4782
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Mechanistic dissection demonstrated that lncRNA SNHG3 facilitated the advance of CRPC by adjusting the expression of PKM2. Further explorations unraveled the role of lncRNA SNHG3 as a 'sponge' of miR-139-5p and released its binding with PKM2 mRNA, leading to PKM2 up-regulation. Together, Our studies suggest that lncRNA SNHG3 / miR-139-5p / PKM4 pathway promotes the development of CRPC via regulating glycolysis process and provides valuable insight into a novel therapeutic approach for the disordered disease.

Disease Class: Castration-resistant prostate cancer [ICD-11: 2C82.0] [6]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Castration-resistant prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Enzalutamide
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Central carbon metabolism in cancer; Activation; hsa05230
• In Vivo Model: 4-weeks-old male nude mice, with empty vector, sh-LncRNA SNHG3, sh-PKM2, sh-LncRNA SNHG3 + sh-PKM4 were separately injected; Mice
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Tumor weight assay
• Mechanism Description: Mechanistic dissection demonstrated that lncRNA SNHG3 facilitated the advance of CRPC by adjusting the expression of PKM2. Further explorations unraveled the role of lncRNA SNHG3 as a 'sponge' of miR-139-5p and released its binding with PKM2 mRNA, leading to PKM2 up-regulation. Together, Our studies suggest that lncRNA SNHG3 / miR-139-5p / PKM7 pathway promotes the development of CRPC via regulating glycolysis process and provides valuable insight into a novel therapeutic approach for the disordered disease.

Methotrexate

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Liver cancer [ICD-11: 2C12.6] [7]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Sensitive Drug: Methotrexate
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Curcumin mediated the amputation of chemoresistance by repressing the hyperglycolytic behavior of malignant cells via modulated expression of metabolic enzymes (HkII, PFk1, GAPDH, PkM2, LDH, SDH, IDH, and FASN), transporters (GLUT-1, MCT-1, and MCT-4), and their regulators. Along altered constitution of extracellular milieu, these molecular changes culminated into improved drug accumulation, chromatin condensation, and induction of cell death.

Preclinical Drug(s) 1 drug(s) in total

HA344

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Cutaneous metastatic melanoma [ICD-11: 2E08.0] [8]

• Metabolic Type: Glucose metabolism
• Sensitive Disease: Cutaneous metastatic melanoma [ICD-11: 2E08.0]
• Sensitive Drug: HA344
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: SkMEL28 cells; Skin; Homo sapiens (Human); CVCL_0526
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: the mechanism of action of HA344 provides potential therapeutic avenues for patients with CMM and a broad range of different cancers

Disease Class: Cutaneous metastatic melanoma [ICD-11: 2E08.0] [8]

• Metabolic Type: Glucose metabolism
• Sensitive Disease: Cutaneous metastatic melanoma [ICD-11: 2E08.0]
• Sensitive Drug: HA344
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: A375 S cells, Five weeks old female athymic nude mice; A375R cells, Five weeks old female athymic nude mice; Mice
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: the mechanism of action of HA344 provides potential therapeutic avenues for patients with CMM and a broad range of different cancers

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Liver cancer [ICD-11: 2C12]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Liver
• The Specified Disease: Liver cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.02E-21; Fold-change: 5.94E-01; Z-score: 1.76E+00
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 2.91E-28; Fold-change: 6.67E-01; Z-score: 1.15E+00
• The Expression Level of Disease Section Compare with the Other Disease Section: p-value: 5.92E-02; Fold-change: 9.88E-01; Z-score: 1.22E+00

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: 1.61E-14; Fold-change: 4.12E-01; Z-score: 1.03E+00
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 2.66E-05; Fold-change: 2.69E-01; Z-score: 4.90E-01

Breast cancer [ICD-11: 2C60]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Breast tissue
• The Specified Disease: Breast cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.62E-40; Fold-change: 8.25E-01; Z-score: 9.43E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 6.74E-06; Fold-change: 5.66E-01; Z-score: 6.07E-01

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: 9.69E-03; Fold-change: 7.25E-01; Z-score: 1.44E+00
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 3.23E-04; Fold-change: 1.57E+00; Z-score: 1.85E+00

References

• Ref 1: MiR-374b re-sensitizes hepatocellular carcinoma cells to sorafenib therapy by antagonizing PKM2-mediated glycolysis pathway. Am J Cancer Res. 2019 Apr 1;9(4):765-778. eCollection 2019.
• Ref 2: Metabolic reprograming confers tamoxifen resistance in breast cancer. Chem Biol Interact. 2021 Sep 25;347:109602. doi: 10.1016/j.cbi.2021.109602. Epub 2021 Jul 28.
• Ref 3: Quantitative proteome analysis of multidrug resistance in human ovarian cancer cell line. J Cell Biochem. 2010 Mar 1;109(4):625-33. doi: 10.1002/jcb.22413.
• Ref 4: [MiR-133b Affect the Proliferation and Drug Sensitivity in A549 Lung Cancer Stem Cells by Targeting PKM2]. Zhongguo Fei Ai Za Zhi. 2017 Jun 20;20(6):376-381. doi: 10.3779/j.issn.1009-3419.2017.06.02.
• Ref 5: MiR-122 Reverses the Doxorubicin-Resistance in Hepatocellular Carcinoma Cells through Regulating the Tumor Metabolism. PLoS One. 2016 May 3;11(5):e0152090. doi: 10.1371/journal.pone.0152090. eCollection 2016.
• Ref 6: Glycolysis related lncRNA SNHG3 / miR-139-5p / PKM2 axis promotes castration-resistant prostate cancer (CRPC) development and enzalutamide resistance. Int J Biol Macromol. 2024 Mar;260(Pt 2):129635.
• Ref 7: Counteracting Action of Curcumin on High Glucose-Induced Chemoresistance in Hepatic Carcinoma Cells. Front Oncol. 2021 Oct 6;11:738961. doi: 10.3389/fonc.2021.738961. eCollection 2021.
• Ref 8: Dual Covalent Inhibition of PKM and IMPDH Targets Metabolism in Cutaneous Metastatic Melanoma. Cancer Res. 2021 Jul 15;81(14):3806-3821.