Ferroptosis Regulator Information

General Information of the Ferroptosis Regulator (ID: REG10173)
Regulator Name 5'-AMP-activated protein kinase catalytic subunit alpha-2 (PRKAA2)
Synonyms
AMPK, AMPK2; Acetyl-CoA carboxylase kinase; Hydroxymethylglutaryl-CoA reductase kinase
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Gene Name PRKAA2
Gene ID 5563
Regulator Type Protein coding
Uniprot ID P54646
Sequence
MAEKQKHDGRVKIGHYVLGDTLGVGTFGKVKIGEHQLTGHKVAVKILNRQKIRSLDVVGK
IKREIQNLKLFRHPHIIKLYQVISTPTDFFMVMEYVSGGELFDYICKHGRVEEMEARRLF
QQILSAVDYCHRHMVVHRDLKPENVLLDAHMNAKIADFGLSNMMSDGEFLRTSCGSPNYA
APEVISGRLYAGPEVDIWSCGVILYALLCGTLPFDDEHVPTLFKKIRGGVFYIPEYLNRS
VATLLMHMLQVDPLKRATIKDIREHEWFKQDLPSYLFPEDPSYDANVIDDEAVKEVCEKF
ECTESEVMNSLYSGDPQDQLAVAYHLIIDNRRIMNQASEFYLASSPPSGSFMDDSAMHIP
PGLKPHPERMPPLIADSPKARCPLDALNTTKPKSLAVKKAKWHLGIRSQSKPYDIMAEVY
RAMKQLDFEWKVVNAYHLRVRRKNPVTGNYVKMSLQLYLVDNRSYLLDFKSIDDEVVEQR
SGSSTPQRSCSAAGLHRPRSSFDSTTAESHSLSGSLTGSLTGSTLSSVSPRLGSHTMDFF
EMCASLITTLAR

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Family CAMK Ser/Thr protein kinase family
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. 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. Promotes lipolysis of lipid droplets by mediating phosphorylation of isoform 1 of CHKA (CHKalpha2). 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/WIPI4. Phosphorylates CASP6, thereby preventing its autoprocessing and subsequent activation. 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 acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin. 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.

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HGNC ID
HGNC:9377
KEGG ID hsa:5563
Full List of the Ferroptosis Target of This Regulator and Corresponding Disease/Drug Response(s)
PRKAA2 can regulate the following target(s), and cause disease/drug response(s). You can browse detail information of target(s) or disease/drug response(s).
Browse Target
Browse Disease
Browse Drug
Cystine/glutamate transporter (SLC7A11) [Driver; Suppressor]
 Target Info 
In total 2 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [1]
Target for Ferroptosis Suppressor
Responsed Disease Colon cancer ICD-11: 2B90
 Disease Info 
Responsed Drug Sulfasalazine Investigative
 Drug Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
AMPK signaling pathway hsa04152
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model
 HCT 116 cells Colon carcinoma Homo sapiens CVCL_0291
PANC-1 cells Pancreatic ductal adenocarcinoma Homo sapiens CVCL_0480
HT-1080 cells Fibrosarcoma Homo sapiens CVCL_0317
Calu-1 cells Lung squamous cell carcinoma Homo sapiens CVCL_0608
HeLa cells Endocervical adenocarcinoma Homo sapiens CVCL_0030
HEK-293T cells Normal Homo sapiens CVCL_0063
In Vivo Model
To generate murine subcutaneous tumors, 5 x 106 HCT116, CX-1, or HT1080 cells in 100 ul phosphate buffered saline (PBS; Thermo Fisher Scientific, AM9625) were injected subcutaneously right of the dorsal midline in athymic nude immunodeficient mice (six- to eight-week-old, female). To generate orthotopic tumors, 1 x 106 KPC cells in 10 ul PBS were surgically implanted into the pancreases of immunocompetent C57BL/6J mice (six- to eight-week-old, female).

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Response regulation BECN1 plays a novel role in lipid peroxidation that could be exploited to improve anticancer therapy by the induction of ferroptosis. Mechanistically, phosphorylation of BECN1 at Ser90/93/96 by PRKAA/ AMPK contributes to the formation of a BECN1-SLC7A11 complex and system Xc-inhibition. Knockdown of BECN1 by shRNA inhibits ferroptosis induced by system X-c- inhibitors (e.g., erastin, sulfasalazine, and sorafenib) in Colon carcinoma.
Experiment 2 Reporting the Ferroptosis Target of This Regulator [1]
Target for Ferroptosis Suppressor
Responsed Disease Colon cancer ICD-11: 2B90
 Disease Info 
Responsed Drug Sulfasalazine Investigative
 Drug Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
AMPK signaling pathway hsa04152
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model
 HCT 116 cells Colon carcinoma Homo sapiens CVCL_0291
PANC-1 cells Pancreatic ductal adenocarcinoma Homo sapiens CVCL_0480
HT-1080 cells Fibrosarcoma Homo sapiens CVCL_0317
Calu-1 cells Lung squamous cell carcinoma Homo sapiens CVCL_0608
HeLa cells Endocervical adenocarcinoma Homo sapiens CVCL_0030
HEK-293T cells Normal Homo sapiens CVCL_0063
In Vivo Model
To generate murine subcutaneous tumors, 5 x 106 HCT116, CX-1, or HT1080 cells in 100 ul phosphate buffered saline (PBS; Thermo Fisher Scientific, AM9625) were injected subcutaneously right of the dorsal midline in athymic nude immunodeficient mice (six- to eight-week-old, female). To generate orthotopic tumors, 1 x 106 KPC cells in 10 ul PBS were surgically implanted into the pancreases of immunocompetent C57BL/6J mice (six- to eight-week-old, female).

    Click to Show/Hide
Response regulation BECN1 plays a novel role in lipid peroxidation that could be exploited to improve anticancer therapy by the induction of ferroptosis. Mechanistically, phosphorylation of BECN1 at Ser90/93/96 by PRKAA/AMPK contributes to the formation of a BECN1-SLC7A11 complex and system Xc-inhibition. Knockdown of BECN1 by shRNA inhibits ferroptosis induced by system X-c- inhibitors (e.g., erastin, sulfasalazine, and sorafenib) in Colon carcinoma.
Unspecific Target [Unspecific Target]
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [2]
Responsed Disease Cardiomyopathy ICD-11: BC43
 Disease Info 
Responsed Drug Epigallocatechin Gallate Investigative
 Drug Info 
Pathway Response Ferroptosis hsa04216
Autophagy hsa04140
mTOR signaling pathway hsa04150
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model
 CHO-S/H9C2 cells Normal Cricetulus griseus CVCL_A0TS
In Vivo Model
Mice were reseparated into 5 groups: control, Dox, Dox + Fer-1, Dox + EGCG, and Dox + EGCG+compound C groups. The Dox group mice were administered 6 intraperitoneal (ip) injections of 2.5 mg/kg Dox over 3 weeks for a cumulative dose of 15 mg/kg. Mice in the Dox + Fer-1 group were ip injected with 1 mg/kg/d Fer-1 for 2 weeks as in the Dox group. Mice in the Dox + EGCG group were intragastrically (ig) injected 20 mg/kg/d EGCG (dissolved in normal saline) for six consecutive weeks; Dox was administered 1 h prior to this as in the Dox group. Mice in the Dox + EGCG + compound C group were treated using the same method as in the Dox + EGCG group for four consecutive weeks, followed by ip injections of 10 mg/kg/d compound C for 2 weeks. Mice in the control groups were administered an equal volume of normal saline via gavage for 6 weeks.

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Response regulation Epigallocatechin-3-gallate pretreatment upregulated the expression and phosphorylation of AMPK2 and activated adaptive autophagy, thus decreasing iron accumulation, inhibiting excess ROS generation and abnormal lipid metabolism, increasing energy supply, and maintaining mitochondrial function, ultimately protecting the myocardium against Dox-induced cardiotoxicity (DIC)-induced ferroptosis.
Colon cancer [ICD-11: 2B90]
 Disease Info 
In total 2 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [1]
Target Regulator 5'-AMP-activated protein kinase catalytic subunit alpha-2 (PRKAA2) Protein coding
 Regulator Info 
Responsed Drug Sulfasalazine Investigative
 Drug Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
AMPK signaling pathway hsa04152
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model
 HCT 116 cells Colon carcinoma Homo sapiens CVCL_0291
PANC-1 cells Pancreatic ductal adenocarcinoma Homo sapiens CVCL_0480
HT-1080 cells Fibrosarcoma Homo sapiens CVCL_0317
Calu-1 cells Lung squamous cell carcinoma Homo sapiens CVCL_0608
HeLa cells Endocervical adenocarcinoma Homo sapiens CVCL_0030
HEK-293T cells Normal Homo sapiens CVCL_0063
In Vivo Model
To generate murine subcutaneous tumors, 5 x 106 HCT116, CX-1, or HT1080 cells in 100 ul phosphate buffered saline (PBS; Thermo Fisher Scientific, AM9625) were injected subcutaneously right of the dorsal midline in athymic nude immunodeficient mice (six- to eight-week-old, female). To generate orthotopic tumors, 1 x 106 KPC cells in 10 ul PBS were surgically implanted into the pancreases of immunocompetent C57BL/6J mice (six- to eight-week-old, female).

    Click to Show/Hide
Response regulation BECN1 plays a novel role in lipid peroxidation that could be exploited to improve anticancer therapy by the induction of ferroptosis. Mechanistically, phosphorylation of BECN1 at Ser90/93/96 by PRKAA/ AMPK contributes to the formation of a BECN1-SLC7A11 complex and system Xc-inhibition. Knockdown of BECN1 by shRNA inhibits ferroptosis induced by system X-c- inhibitors (e.g., erastin, sulfasalazine, and sorafenib) in Colon carcinoma.
Experiment 2 Reporting the Ferroptosis-centered Disease Response [1]
Target Regulator 5'-AMP-activated protein kinase catalytic subunit alpha-2 (PRKAA2) Protein coding
 Regulator Info 
Responsed Drug Sulfasalazine Investigative
 Drug Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
AMPK signaling pathway hsa04152
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model
 HCT 116 cells Colon carcinoma Homo sapiens CVCL_0291
PANC-1 cells Pancreatic ductal adenocarcinoma Homo sapiens CVCL_0480
HT-1080 cells Fibrosarcoma Homo sapiens CVCL_0317
Calu-1 cells Lung squamous cell carcinoma Homo sapiens CVCL_0608
HeLa cells Endocervical adenocarcinoma Homo sapiens CVCL_0030
HEK-293T cells Normal Homo sapiens CVCL_0063
In Vivo Model
To generate murine subcutaneous tumors, 5 x 106 HCT116, CX-1, or HT1080 cells in 100 ul phosphate buffered saline (PBS; Thermo Fisher Scientific, AM9625) were injected subcutaneously right of the dorsal midline in athymic nude immunodeficient mice (six- to eight-week-old, female). To generate orthotopic tumors, 1 x 106 KPC cells in 10 ul PBS were surgically implanted into the pancreases of immunocompetent C57BL/6J mice (six- to eight-week-old, female).

    Click to Show/Hide
Response regulation BECN1 plays a novel role in lipid peroxidation that could be exploited to improve anticancer therapy by the induction of ferroptosis. Mechanistically, phosphorylation of BECN1 at Ser90/93/96 by PRKAA/AMPK contributes to the formation of a BECN1-SLC7A11 complex and system Xc-inhibition. Knockdown of BECN1 by shRNA inhibits ferroptosis induced by system X-c- inhibitors (e.g., erastin, sulfasalazine, and sorafenib) in Colon carcinoma.
Cardiomyopathy [ICD-11: BC43]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [2]
Target Regulator 5'-AMP-activated protein kinase catalytic subunit alpha-2 (PRKAA2) Protein coding
 Regulator Info 
Responsed Drug Epigallocatechin Gallate Investigative
 Drug Info 
Pathway Response Ferroptosis hsa04216
Autophagy hsa04140
mTOR signaling pathway hsa04150
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model
 CHO-S/H9C2 cells Normal Cricetulus griseus CVCL_A0TS
In Vivo Model
Mice were reseparated into 5 groups: control, Dox, Dox + Fer-1, Dox + EGCG, and Dox + EGCG+compound C groups. The Dox group mice were administered 6 intraperitoneal (ip) injections of 2.5 mg/kg Dox over 3 weeks for a cumulative dose of 15 mg/kg. Mice in the Dox + Fer-1 group were ip injected with 1 mg/kg/d Fer-1 for 2 weeks as in the Dox group. Mice in the Dox + EGCG group were intragastrically (ig) injected 20 mg/kg/d EGCG (dissolved in normal saline) for six consecutive weeks; Dox was administered 1 h prior to this as in the Dox group. Mice in the Dox + EGCG + compound C group were treated using the same method as in the Dox + EGCG group for four consecutive weeks, followed by ip injections of 10 mg/kg/d compound C for 2 weeks. Mice in the control groups were administered an equal volume of normal saline via gavage for 6 weeks.

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Response regulation Epigallocatechin-3-gallate pretreatment upregulated the expression and phosphorylation of AMPK2 and activated adaptive autophagy, thus decreasing iron accumulation, inhibiting excess ROS generation and abnormal lipid metabolism, increasing energy supply, and maintaining mitochondrial function, ultimately protecting the myocardium against Dox-induced cardiotoxicity (DIC)-induced ferroptosis.
Sulfasalazine [Investigative]
 Drug Info 
In total 2 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response [1]
Drug for Ferroptosis Inducer
Response Target Cystine/glutamate transporter (SLC7A11) Driver; Suppressor
 Target Info 
Responsed Disease Colon cancer ICD-11: 2B90
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
AMPK signaling pathway hsa04152
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model
 HCT 116 cells Colon carcinoma Homo sapiens CVCL_0291
PANC-1 cells Pancreatic ductal adenocarcinoma Homo sapiens CVCL_0480
HT-1080 cells Fibrosarcoma Homo sapiens CVCL_0317
Calu-1 cells Lung squamous cell carcinoma Homo sapiens CVCL_0608
HeLa cells Endocervical adenocarcinoma Homo sapiens CVCL_0030
HEK-293T cells Normal Homo sapiens CVCL_0063
In Vivo Model
To generate murine subcutaneous tumors, 5 x 106 HCT116, CX-1, or HT1080 cells in 100 ul phosphate buffered saline (PBS; Thermo Fisher Scientific, AM9625) were injected subcutaneously right of the dorsal midline in athymic nude immunodeficient mice (six- to eight-week-old, female). To generate orthotopic tumors, 1 x 106 KPC cells in 10 ul PBS were surgically implanted into the pancreases of immunocompetent C57BL/6J mice (six- to eight-week-old, female).

    Click to Show/Hide
Response regulation BECN1 plays a novel role in lipid peroxidation that could be exploited to improve anticancer therapy by the induction of ferroptosis. Mechanistically, phosphorylation of BECN1 at Ser90/93/96 by PRKAA/ AMPK contributes to the formation of a BECN1-SLC7A11 complex and system Xc-inhibition. Knockdown of BECN1 by shRNA inhibits ferroptosis induced by system X-c- inhibitors (e.g., erastin, sulfasalazine, and sorafenib) in Colon carcinoma.
Experiment 2 Reporting the Ferroptosis-centered Drug Response [1]
Drug for Ferroptosis Inducer
Response Target Cystine/glutamate transporter (SLC7A11) Driver; Suppressor
 Target Info 
Responsed Disease Colon cancer ICD-11: 2B90
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
AMPK signaling pathway hsa04152
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model
 HCT 116 cells Colon carcinoma Homo sapiens CVCL_0291
PANC-1 cells Pancreatic ductal adenocarcinoma Homo sapiens CVCL_0480
HT-1080 cells Fibrosarcoma Homo sapiens CVCL_0317
Calu-1 cells Lung squamous cell carcinoma Homo sapiens CVCL_0608
HeLa cells Endocervical adenocarcinoma Homo sapiens CVCL_0030
HEK-293T cells Normal Homo sapiens CVCL_0063
In Vivo Model
To generate murine subcutaneous tumors, 5 x 106 HCT116, CX-1, or HT1080 cells in 100 ul phosphate buffered saline (PBS; Thermo Fisher Scientific, AM9625) were injected subcutaneously right of the dorsal midline in athymic nude immunodeficient mice (six- to eight-week-old, female). To generate orthotopic tumors, 1 x 106 KPC cells in 10 ul PBS were surgically implanted into the pancreases of immunocompetent C57BL/6J mice (six- to eight-week-old, female).

    Click to Show/Hide
Response regulation BECN1 plays a novel role in lipid peroxidation that could be exploited to improve anticancer therapy by the induction of ferroptosis. Mechanistically, phosphorylation of BECN1 at Ser90/93/96 by PRKAA/AMPK contributes to the formation of a BECN1-SLC7A11 complex and system Xc-inhibition. Knockdown of BECN1 by shRNA inhibits ferroptosis induced by system X-c- inhibitors (e.g., erastin, sulfasalazine, and sorafenib) in Colon carcinoma.
Epigallocatechin Gallate [Investigative]
 Drug Info 
In total 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response [2]
Drug for Ferroptosis Suppressor
Response Target Unspecific Target
Responsed Disease Cardiomyopathy ICD-11: BC43
 Disease Info 
Pathway Response Ferroptosis hsa04216
Autophagy hsa04140
mTOR signaling pathway hsa04150
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model
 CHO-S/H9C2 cells Normal Cricetulus griseus CVCL_A0TS
In Vivo Model
Mice were reseparated into 5 groups: control, Dox, Dox + Fer-1, Dox + EGCG, and Dox + EGCG+compound C groups. The Dox group mice were administered 6 intraperitoneal (ip) injections of 2.5 mg/kg Dox over 3 weeks for a cumulative dose of 15 mg/kg. Mice in the Dox + Fer-1 group were ip injected with 1 mg/kg/d Fer-1 for 2 weeks as in the Dox group. Mice in the Dox + EGCG group were intragastrically (ig) injected 20 mg/kg/d EGCG (dissolved in normal saline) for six consecutive weeks; Dox was administered 1 h prior to this as in the Dox group. Mice in the Dox + EGCG + compound C group were treated using the same method as in the Dox + EGCG group for four consecutive weeks, followed by ip injections of 10 mg/kg/d compound C for 2 weeks. Mice in the control groups were administered an equal volume of normal saline via gavage for 6 weeks.

    Click to Show/Hide
Response regulation Epigallocatechin-3-gallate pretreatment upregulated the expression and phosphorylation of AMPK2 and activated adaptive autophagy, thus decreasing iron accumulation, inhibiting excess ROS generation and abnormal lipid metabolism, increasing energy supply, and maintaining mitochondrial function, ultimately protecting the myocardium against Dox-induced cardiotoxicity (DIC)-induced ferroptosis.
References
Ref 1 AMPK-Mediated BECN1 Phosphorylation Promotes Ferroptosis by Directly Blocking System X(c)(-) Activity. Curr Biol. 2018 Aug 6;28(15):2388-2399.e5. doi: 10.1016/j.cub.2018.05.094. Epub 2018 Jul 26.
Ref 2 Epigallocatechin-3-gallate pretreatment alleviates doxorubicin-induced ferroptosis and cardiotoxicity by upregulating AMPK2 and activating adaptive autophagy. Redox Biol. 2021 Nov 11;48:102185. doi: 10.1016/j.redox.2021.102185. Online ahead of print.