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PXD035007-2

PXD035007 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleEndoxifen Downregulates AKT Phosphorylation Through Protein Kinase C Beta 1 in ER+/HER2- Breast Cancer
DescriptionIn phase I/II clinical trials, Z-endoxifen demonstrated substantial oral bioavailability and promising antitumor activity in endocrine-refractory estrogen-receptor positive breast cancer (ER+ BC) and other solid tumors, with plasma concentrations reportedly as high as 5 �M. Therefore, we explored the potential mechanisms of Z-endoxifen antitumor activity that extends beyond ERα inhibition. In estrogen unstimulated aromatase-expressing ER+/human epidermal growth factor 2 receptor negative (HER2-) MCF7AC1 BC cells, Z-endoxifen at 5 �M, but not ER�-targeting 0.01 and 0.1 �M concentrations inhibited growth and induced apoptosis, suggesting an ERα-independent effect. Utilizing an unbiased mass spectrometry approach, we explored Z-endoxifen effects on other signaling pathways. Z-endoxifen at 5 µM profoundly altered the phosphoproteome with minimal impact on total proteome. Computational analysis revealed Protein kinase C beta (PKC�) and AKT1 as the prevalent upstream kinases for Z-endoxifen-downregulated protein phosphorylations. Notably, in ER+/HER2- BC models, Z-endoxifen at 5 �M attenuated AKTSer473 and AKT substrates in vitro in the presence of insulin and PKC agonist PMA and in vivo. Further, Z-endoxifen inhibited PKC�1 kinase activity compared to other PKC isoforms in vitro and bound to PKCβ1. While PMA stimulated PKC�1Ser661 phosphorylation correlated with AKTSer473 and AKT substrate phosphorylation, Z-endoxifen at 5 �M uniquely blocked these effects and induced PKCβ1 protein degradation. siRNA-mediated PKC�1 knockdown attenuated AKTSer473 phosphorylation, suggesting PKCβ1-mediated suppression of AKT signaling by Z-endoxifen. Further, Z-endoxifen at 5 �M replicates the pan-AKT inhibitor MK-2206 effects on apoptosis. These findings implicate PKCβ1 as a novel Z-endoxifen substrate responsible for suppressing AKT signaling and inducing apoptosis in breast cancer.
HostingRepositoryPRIDE
AnnounceDate2024-10-22
AnnouncementXMLSubmission_2024-10-22_06:25:43.269.xml
DigitalObjectIdentifierhttps://dx.doi.org/10.6019/PXD035007
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportSupported dataset by repository
PrimarySubmitterAkhilesh Pandey
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListphosphorylated residue; acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
InstrumentOrbitrap Fusion Lumos
Dataset History
RevisionDatetimeStatusChangeLog Entry
02022-06-30 03:18:06ID requested
12024-01-26 06:54:02announced
22024-10-22 06:25:44announced2024-10-22: Updated project metadata.
Publication List
Jayaraman S, Wu X, Kalari KR, Tang X, Kuffel MJ, Bruinsma ES, Jalali S, Peterson KL, Correia C, Kudgus RA, Kaufmann SH, Renuse S, Ingle JN, Reid JM, Ames MM, Fields AP, Schellenberg MJ, Hawse JR, Pandey A, Goetz MP, + breast cancer. NPJ Breast Cancer, 9(1):101(2023) [pubmed]
10.1038/s41523-023-00606-2;
10.6019/PXD035007;
Keyword List
submitter keyword: breast cancer,Endoxifen, Mass Spectrometry, PKC-beta-1, AKT, Apoptosis, Phosphoproteome
Contact List
Akhilesh Pandey
contact affiliationLaboratory Medicine and Pathology Mayo Clinic USA
contact emailpandey.akhilesh@mayo.edu
lab head
Akhilesh Pandey
contact affiliationDepartment of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905
contact emailpandey.akhilesh@mayo.edu
dataset submitter
Full Dataset Link List
Dataset FTP location
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