Molecule Information

General Information of the Molecule (ID: Mol01827)

• Name: AMP-activated kinase alpha-2 (PRKAA2) ,Homo sapiens
• Synonyms: AMPK subunit alpha-2; Acetyl-CoA carboxylase kinase; ACACA kinase; Hydroxymethylglutaryl-CoA reductase kinase; HMGCR kinase; PRKAA2; AMPK; AMPK2
• Molecule Type: Protein
• Gene Name: PRKAA2
• Gene ID: 5563
• Location: chr3:56,645,314-56,715,335[+]
• Sequence:
  MAEKQKHDGRVKIGHYVLGDTLGVGTFGKVKIGEHQLTGHKVAVKILNRQKIRSLDVVGK
  IKREIQNLKLFRHPHIIKLYQVISTPTDFFMVMEYVSGGELFDYICKHGRVEEMEARRLF
  QQILSAVDYCHRHMVVHRDLKPENVLLDAHMNAKIADFGLSNMMSDGEFLRTSCGSPNYA
  APEVISGRLYAGPEVDIWSCGVILYALLCGTLPFDDEHVPTLFKKIRGGVFYIPEYLNRS
  VATLLMHMLQVDPLKRATIKDIREHEWFKQDLPSYLFPEDPSYDANVIDDEAVKEVCEKF
  ECTESEVMNSLYSGDPQDQLAVAYHLIIDNRRIMNQASEFYLASSPPSGSFMDDSAMHIP
  PGLKPHPERMPPLIADSPKARCPLDALNTTKPKSLAVKKAKWHLGIRSQSKPYDIMAEVY
  RAMKQLDFEWKVVNAYHLRVRRKNPVTGNYVKMSLQLYLVDNRSYLLDFKSIDDEVVEQR
  SGSSTPQRSCSAAGLHRPRSSFDSTTAESHSLSGSLTGSLTGSTLSSVSPRLGSHTMDFF
  EMCASLITTLAR
• 3D-structure: PDB ID: 4CFE; Classification: Transferase; Method: X-ray diffraction; Resolution: 3.02 Å
• Function: Catalytic subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism. In response to reduction of intracellular ATP levels, AMPK activates energy-producing pathways and inhibits energy-consuming processes: inhibits protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation. AMPK acts via direct phosphorylation of metabolic enzymes, and by longer-term effects via phosphorylation of transcription regulators. Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin. Regulates lipid synthesis by phosphorylating and inactivating lipid metabolic enzymes such as ACACA, ACACB, GYS1, HMGCR and LIPE; regulates fatty acid and cholesterol synthesis by phosphorylating acetyl-CoA carboxylase (ACACA and ACACB) and hormone-sensitive lipase (LIPE) enzymes, respectively. Regulates insulin-signaling and glycolysis by phosphorylating IRS1, PFKFB2 and PFKFB3. Involved in insulin receptor/INSR internalization. AMPK stimulates glucose uptake in muscle by increasing the translocation of the glucose transporter SLC2A4/GLUT4 to the plasma membrane, possibly by mediating phosphorylation of TBC1D4/AS160. Regulates transcription and chromatin structure by phosphorylating transcription regulators involved in energy metabolism such as CRTC2/TORC2, FOXO3, histone H2B, HDAC5, MEF2C, MLXIPL/ChREBP, EP300, HNF4A, p53/TP53, SREBF1, SREBF2 and PPARGC1A. Acts as a key regulator of glucose homeostasis in liver by phosphorylating CRTC2/TORC2, leading to CRTC2/TORC2 sequestration in the cytoplasm. In response to stress, phosphorylates 'Ser-36' of histone H2B (H2BS36ph), leading to promote transcription. Acts as a key regulator of cell growth and proliferation by phosphorylating TSC2, RPTOR and ATG1/ULK1: in response to nutrient limitation, negatively regulates the mTORC1 complex by phosphorylating RPTOR component of the mTORC1 complex and by phosphorylating and activating TSC2. In response to nutrient limitation, promotes autophagy by phosphorylating and activating ATG1/ULK1. In that process also activates WDR45. AMPK also acts as a regulator of circadian rhythm by mediating phosphorylation of CRY1, leading to destabilize it. May regulate the Wnt signaling pathway by phosphorylating CTNNB1, leading to stabilize it. Also phosphorylates CFTR, EEF2K, KLC1, NOS3 and SLC12A1. Plays an important role in the differential regulation of pro-autophagy (composed of PIK3C3, BECN1, PIK3R4 and UVRAG or ATG14) and non-autophagy (composed of PIK3C3, BECN1 and PIK3R4) complexes, in response to glucose starvation. Can inhibit the non-autophagy complex by phosphorylating PIK3C3 and can activate the pro-autophagy complex by phosphorylating BECN1.
• Uniprot ID: AAPK2_HUMAN
• Ensembl ID: ENSG00000162409
• HGNC ID: HGNC:9377

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

Capsaicin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Tongue squamous cell carcinoma [ICD-11: 2B62.0] [1]

• Metabolic Type: Glucose metabolism
• Sensitive Disease: Tongue squamous cell carcinoma [ICD-11: 2B62.0]
• Sensitive Drug: Capsaicin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: mTOR signaling pathway; Activation; hsa04150
• Cell Pathway Regulation: AMPK signaling pathway; Activation; hsa04152
• Cell Pathway Regulation: Insulin signaling pathway; Activation; hsa04910
• In Vivo Model: Tumor xenograft model; Mice
• Experiment for Drug Resistance: Tumor weight assay
• Mechanism Description: Overall, combined treatment with capsaicin and cisplatin reversed cisplatin resistance by inhibiting the Warburg effect and facilitating mitochondrial-dependent apoptosis via the AMPK/AKT/mTOR axis.

Disease Class: Tongue squamous cell carcinoma [ICD-11: 2B62.0] [1]

• Metabolic Type: Glucose metabolism
• Sensitive Disease: Tongue squamous cell carcinoma [ICD-11: 2B62.0]
• Sensitive Drug: Capsaicin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: mTOR signaling pathway; Activation; hsa04150
• Cell Pathway Regulation: AMPK signaling pathway; Activation; hsa04152
• Cell Pathway Regulation: Insulin signaling pathway; Activation; hsa04910
• In Vitro Model: CAL27 cells; Oral; Homo sapiens (Human); CVCL_1107
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Overall, combined treatment with capsaicin and cisplatin reversed cisplatin resistance by inhibiting the Warburg effect and facilitating mitochondrial-dependent apoptosis via the AMPK/AKT/mTOR axis.

Cisplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Tongue squamous cell carcinoma [ICD-11: 2B62.0] [1]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Tongue squamous cell carcinoma [ICD-11: 2B62.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: mTOR signaling pathway; Activation; hsa04150
• Cell Pathway Regulation: AMPK signaling pathway; Activation; hsa04152
• Cell Pathway Regulation: Insulin signaling pathway; Activation; hsa04910
• In Vivo Model: Tumor xenograft model; Mice
• Experiment for Drug Resistance: Tumor weight assay
• Mechanism Description: Overall, combined treatment with capsaicin and cisplatin reversed cisplatin resistance by inhibiting the Warburg effect and facilitating mitochondrial-dependent apoptosis via the AMPK/AKT/mTOR axis.

Disease Class: Tongue squamous cell carcinoma [ICD-11: 2B62.0] [1]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Tongue squamous cell carcinoma [ICD-11: 2B62.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: mTOR signaling pathway; Activation; hsa04150
• Cell Pathway Regulation: AMPK signaling pathway; Activation; hsa04152
• Cell Pathway Regulation: Insulin signaling pathway; Activation; hsa04910
• In Vitro Model: CAL27 cells; Oral; Homo sapiens (Human); CVCL_1107
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Overall, combined treatment with capsaicin and cisplatin reversed cisplatin resistance by inhibiting the Warburg effect and facilitating mitochondrial-dependent apoptosis via the AMPK/AKT/mTOR axis.

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

Endoxifen

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Estrogen receptor (ER)-positive breast cancer [ICD-11: 2C60.6] [2]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Estrogen receptor (ER)-positive breast cancer [ICD-11: 2C60.6]
• Resistant Drug: Endoxifen
• Molecule Alteration: Autophosphorylation; T172
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: ER+ MCF7 BC cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: TRC cells; Breast; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Therefore, our results indicate increased activation of AKT and AMPK with metabolic reprogramming and increased autophagy in TAM-resistant cells. Simultaneous inhibition of AKT and FAO/autophagy is necessary to fully sensitize resistant cells to endoxifen.

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

ACLY siRNA

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [3]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: ACLY siRNA
• Molecule Alteration: Other; p.T172(Phosphorylation) (c.514_516)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: The mutation p.T172(Phosphorylation) (c.514_516) in gene PRKAA2 cause the sensitivity of ACLY SiRNA by unusual activation of pro-survival pathway.

References

• Ref 1: Capsaicin reverses cisplatin resistance in tongue squamous cell carcinoma by inhibiting the Warburg effect and facilitating mitochondrial-dependent apoptosis via the AMPK/AKT/mTOR axis. Cell Biol Int. 2024 Aug;48(8):1097-1110.
• Ref 2: Fatty acid oxidation and autophagy promote endoxifen resistance and counter the effect of AKT inhibition in ER-positive breast cancer cells. J Mol Cell Biol. 2021 Sep 11;13(6):433-444.
• Ref 3: Inhibition of ATP citrate lyase induces an anticancer effect via reactive oxygen species: AMPK as a predictive biomarker for therapeutic impactAm J Pathol. 2013 May;182(5):1800-10. doi: 10.1016/j.ajpath.2013.01.048. Epub 2013 Mar 15.