Ferroptosis Target Information

General Information of the Ferroptosis Target (ID: TAR10012)
Target Name Hydroperoxide isomerase ALOXE3 (ALOXE3)
Synonyms
Epidermis-type lipoxygenase 3; Hydroperoxy dehydratase ALOXE3; Hydroperoxy icosatetraenoate dehydratase; Hydroperoxy icosatetraenoate isomerase
    Click to Show/Hide
Gene Name ALOXE3
Sequence
MAVYRLCVTTGPYLRAGTLDNISVTLVGTCGESPKQRLDRMGRDFAPGSVQKYKVRCTAE
LGELLLLRVHKERYAFFRKDSWYCSRICVTEPDGSVSHFPCYQWIEGYCTVELRPGTART
ICQDSLPLLLDHRTRELRARQECYRWKIYAPGFPCMVDVNSFQEMESDKKFALTKTTTCV
DQGDSSGNRYLPGFPMKIDIPSLMYMEPNVRYSATKTISLLFNAIPASLGMKLRGLLDRK
GSWKKLDDMQNIFWCHKTFTTKYVTEHWCEDHFFGYQYLNGVNPVMLHCISSLPSKLPVT
NDMVAPLLGQDTCLQTELERGNIFLADYWILAEAPTHCLNGRQQYVAAPLCLLWLSPQGA
LVPLAIQLSQTPGPDSPIFLPTDSEWDWLLAKTWVRNSEFLVHENNTHFLCTHLLCEAFA
MATLRQLPLCHPIYKLLLPHTRYTLQVNTIARATLLNPEGLVDQVTSIGRQGLIYLMSTG
LAHFTYTNFCLPDSLRARGVLAIPNYHYRDDGLKIWAAIESFVSEIVGYYYPSDASVQQD
SELQAWTGEIFAQAFLGRESSGFPSRLCTPGEMVKFLTAIIFNCSAQHAAVNSGQHDFGA
WMPNAPSSMRQPPPQTKGTTTLKTYLDTLPEVNISCNNLLLFWLVSQEPKDQRPLGTYPD
EHFTEEAPRRSIAAFQSRLAQISRDIQERNQGLALPYTYLDPPLIENSVSI

    Click to Show/Hide
Family Lipoxygenase family
Function
Non-heme iron-containing lipoxygenase which is atypical in that it displays a prominent hydroperoxide isomerase activity and a reduced lipoxygenases activity. The hydroperoxide isomerase activity catalyzes the isomerization of hydroperoxides, derived from arachidonic and linoleic acid by ALOX12B, into hepoxilin-type epoxyalcohols and ketones. In presence of oxygen, oxygenates polyunsaturated fatty acids, including arachidonic acid, to produce fatty acid hydroperoxides. In the skin, acts downstream of ALOX12B on the linoleate moiety of esterified omega-hydroxyacyl-sphingosine (EOS) ceramides to produce an epoxy-ketone derivative, a crucial step in the conjugation of omega-hydroxyceramide to membrane proteins. Therefore plays a crucial role in the synthesis of corneocytes lipid envelope and the establishment of the skin barrier to water loss. In parallel, it may have a signaling function in barrier formation through the production of hepoxilins metabolites. Also plays a role in adipocyte differentiation through hepoxilin A3 and hepoxilin B3 production which in turn activate PPARG. Through the production of hepoxilins in the spinal cord, it may regulate inflammatory tactile allodynia.

    Click to Show/Hide
Gene ID 59344
Uniprot ID
Q9BYJ1
Target Type Driver Suppressor Marker
Mechanism Diagram Click to View the Original Diagram
Tissue Relative Abundances of This Target
Full List of Regulator(s) of This Ferroptosis Target and Corresponding Disease/Drug Response(s)
ALOXE3 can be involved in and affect the ferroptosis by the following regulators, and result in corresponding disease/drug response(s). You can browse corresponding disease or drug response(s) resulting from the regulation of certain regulators.
Browse Regulator related Disease
Browse Regulator related Drug
hsa-mir-18a (Precursor RNA)
 Regulator Info 
Glioblastoma [ICD-11: 2A00]
In total 1 item(s) under this disease
 Disease Info 
Experiment 1 Reporting the Ferroptosis-centered Disease Response of This Regulator [1]
Regulator for Ferroptosis Suppressor
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
Cell migration
In Vitro Model
 U87 MG-Red-Fluc cells Glioblastoma Homo sapiens CVCL_5J12
U-251MG cells Astrocytoma Homo sapiens CVCL_0021
In Vivo Model
The 8-week-old male nude mice were randomly divided into two groups (6 mice per group). The investigators were not blinded to the experimental groups. Orthotopic implantation of GBM cells into the hippocampus of nude mice was performed as we previously described (n = 6). Mice were intraperitoneally injected with luciferin (150 mg/kg; catalog #P1043; Promega) and subjected to IVIS Spectrum in vivo imaging system (PerkinElmer) to determine the intracranial tumor size.

    Click to Show/Hide
Response Description MiR-18a/ALOXE3 axis exerts tumor promoting functions by regulating ferroptosis and migration of glioblastoma cells. Mechanistically, miR-18a directly targeted ALOXE3 and suppressed its expression and functions in GBM cells.
Unspecific Regulator
Colorectal cancer [ICD-11: 2B91]
In total 1 item(s) under this disease
 Disease Info 
Experiment 1 Reporting the Ferroptosis-centered Disease Response of This Regulator [2]
Responsed Drug Talaroconvolutin A Investigative
 Drug Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
 HCT 116 cells Colon carcinoma Homo sapiens CVCL_0291
SW480 cells Colon adenocarcinoma Homo sapiens CVCL_0546
SW620 cells Colon adenocarcinoma Homo sapiens CVCL_0547
In Vivo Model
5 x 106 HCT116 cells were inoculated subcutaneously in the underarm of Balb/c nude female mice (5-week old). The inoculated mice were randomly divided into two groups (6 mice each group). When the tumor reached 300 mm3, the drug group was given TalaA intraperitoneally at a dose of 6.0 mg/kg, and the control group was given the same dose of cosolvent-corn oil. The drug (or cosolvent) was injected every 2 days. Body weight and tumor volume were measured every 2 days.

    Click to Show/Hide
Response Description Talaroconvolutin A (TalaA) downregulated the expression of the channel protein solute carrier family 7 member 11 (SLC7A11) but upregulated arachidonate lipoxygenase 3 (ALOXE3), promoting ferroptosis. TalaA causes upregulation of HMOX1 which lead to the degradation of heme and the release of free iron, accumulating in mitochondria and giving rise to lipid peroxidation. TalaA could be a new potential powerful drug candidate for colorectal cancer therapy.
Histone-lysine N-methyltransferase 2D (KMT2D)
 Regulator Info 
Health [ICD-11: N.A.]
In total 1 item(s) under this disease
 Disease Info 
Experiment 1 Reporting the Ferroptosis-centered Disease Response of This Regulator [3]
Regulator for Ferroptosis Driver
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
Cell differentiation
In Vitro Model
 NHEK/SV3 cells Normal Homo sapiens CVCL_9Q50
3T3-J2 cells Normal Mus musculus CVCL_W667
In Vivo Model
All animal protocols were reviewed and approved by the Institutional Animal Care and Use Committee of the University of Pennsylvania. Mice were maintained on a mixed C57BL/6 background on a standard light-dark cycle. Mice carrying Mll4SET floxed alleles, Mll3SET floxed alleles, or a combination of both of these were crossed with Krt14-Cre transgenic mice.

    Click to Show/Hide
Response Description MLL4 (KMT2D) deficiency profoundly alters epidermal gene expression and uniquely rewires the expression of key genes and markers of ferroptosis (Alox12, Alox12b, and Aloxe3).
Unspecific Regulator
Talaroconvolutin A [Investigative]
In total 1 item(s) under this drug
 Drug Info 
Experiment 1 Reporting the Ferroptosis-centered Drug Response of This Regulator [2]
Responsed Disease Colorectal cancer [ICD-11: 2B91]
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model HCT 116 cells Colon carcinoma Homo sapiens CVCL_0291
SW480 cells Colon adenocarcinoma Homo sapiens CVCL_0546
SW620 cells Colon adenocarcinoma Homo sapiens CVCL_0547
In Vivo Model
5 x 106 HCT116 cells were inoculated subcutaneously in the underarm of Balb/c nude female mice (5-week old). The inoculated mice were randomly divided into two groups (6 mice each group). When the tumor reached 300 mm3, the drug group was given TalaA intraperitoneally at a dose of 6.0 mg/kg, and the control group was given the same dose of cosolvent-corn oil. The drug (or cosolvent) was injected every 2 days. Body weight and tumor volume were measured every 2 days.

    Click to Show/Hide
Response Description Talaroconvolutin A (TalaA) downregulated the expression of the channel protein solute carrier family 7 member 11 (SLC7A11) but upregulated arachidonate lipoxygenase 3 (ALOXE3), promoting ferroptosis. TalaA causes upregulation of HMOX1 which lead to the degradation of heme and the release of free iron, accumulating in mitochondria and giving rise to lipid peroxidation. TalaA could be a new potential powerful drug candidate for colorectal cancer therapy.
References
Ref 1 miR-18a promotes glioblastoma development by down-regulating ALOXE3-mediated ferroptotic and anti-migration activities. Oncogenesis. 2021 Feb 12;10(2):15. doi: 10.1038/s41389-021-00304-3.
Ref 2 Discovery of a novel ferroptosis inducer-talaroconvolutin A-killing colorectal cancer cells in vitro and in vivo. Cell Death Dis. 2020 Nov 17;11(11):988. doi: 10.1038/s41419-020-03194-2.
Ref 3 MLL4 mediates differentiation and tumor suppression through ferroptosis. Sci Adv. 2021 Dec 10;7(50):eabj9141. doi: 10.1126/sciadv.abj9141. Epub 2021 Dec 10.