Endoxifen downregulates AKT phosphorylation through protein kinase C beta 1 inhibition in ERα+ breast cancer.

Autor: Jayaraman S; Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA., Wu X; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA.; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, 55905, USA., Kalari KR; Department of Health Sciences Research, Mayo Clinic, Rochester, MN, 55905, USA., Tang X; Department of Health Sciences Research, Mayo Clinic, Rochester, MN, 55905, USA., Kuffel MJ; Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA., Bruinsma ES; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, 55905, USA., Jalali S; Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA., Peterson KL; Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA., Correia C; Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA.; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, 55905, USA., Kudgus RA; Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA., Kaufmann SH; Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA.; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, 55905, USA., Renuse S; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA., Ingle JN; Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA., Reid JM; Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA., Ames MM; Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA.; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, 55905, USA., Fields AP; Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, FL, 32224, USA., Schellenberg MJ; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, 55905, USA., Hawse JR; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, 55905, USA.; Department of Cancer Biology, Mayo Clinic, Rochester, MN, 55905, USA., Pandey A; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA., Goetz MP; Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA. Goetz.Matthew@mayo.edu.; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, 55905, USA. Goetz.Matthew@mayo.edu.
Jazyk: angličtina
Zdroj: NPJ breast cancer [NPJ Breast Cancer] 2023 Dec 19; Vol. 9 (1), pp. 101. Date of Electronic Publication: 2023 Dec 19.
DOI: 10.1038/s41523-023-00606-2
Abstrakt: Endoxifen, a secondary tamoxifen metabolite, is a potent antiestrogen exhibiting estrogen receptor alpha (ERα) binding at nanomolar concentrations. Phase I/II clinical trials identified clinical activity of Z-endoxifen (ENDX), in endocrine-refractory metastatic breast cancer as well as ERα+ solid tumors, raising the possibility that ENDX may have a second, ERα-independent, mechanism of action. An unbiased mass spectrometry approach revealed that ENDX concentrations achieved clinically with direct ENDX administration (5 µM), but not low concentrations observed during tamoxifen treatment (<0.1 µM), profoundly altered the phosphoproteome of the aromatase expressing MCF7AC1 cells with limited impact on the total proteome. Computational analysis revealed protein kinase C beta (PKCβ) and protein kinase B alpha or AKT1 as potential kinases responsible for mediating ENDX effects on protein phosphorylation. ENDX more potently inhibited PKCβ1 kinase activity compared to other PKC isoforms, and ENDX binding to PKCβ1 was confirmed using Surface Plasma Resonance. Under conditions that activated PKC/AKT signaling, ENDX induced PKCβ1 degradation, attenuated PKCβ1-activated AKT Ser473 phosphorylation, diminished AKT substrate phosphorylation, and induced apoptosis. ENDX's effects on AKT were phenocopied by siRNA-mediated PKCβ1 knockdown or treatment with the pan-AKT inhibitor, MK-2206, while overexpression of constitutively active AKT diminished ENDX-induced apoptosis. These findings, which identify PKCβ1 as an ENDX target, indicate that PKCβ1/ENDX interactions suppress AKT signaling and induce apoptosis in breast cancer.
(© 2023. The Author(s).)
Databáze: MEDLINE
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