Tamoxifen Activates Transcription Factor EB and Triggers Protective Autophagy in Breast Cancer Cells by Inducing Lysosomal Calcium Release: A Gateway to the Onset of Endocrine Resistance

Among the several mechanisms accounting for endocrine resistance in breast cancer, autophagy has emerged as an important player. Previous reports have evidenced that tamoxifen (Tam) induces autophagy and activates transcription factor EB (TFEB), which regulates the expression of genes controlling au...

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Published in:International journal of molecular sciences 2023-12, Vol.25 (1), p.458
Main Authors: Boretto, Cecilia, Actis, Chiara, Faris, Pawan, Cordero, Francesca, Beccuti, Marco, Ferrero, Giulio, Muzio, Giuliana, Moccia, Francesco, Autelli, Riccardo
Format: Article
Language:English
Subjects:
Autophagy
Biosynthesis
Breast cancer
calcium signaling
Cancer cells
Cancer therapies
Development and progression
Drug resistance
endocrine resistance
Kinases
Localization
lysosomal calcium channels
Medical prognosis
Tamoxifen
TFEB
Transcription factors
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Summary:Among the several mechanisms accounting for endocrine resistance in breast cancer, autophagy has emerged as an important player. Previous reports have evidenced that tamoxifen (Tam) induces autophagy and activates transcription factor EB (TFEB), which regulates the expression of genes controlling autophagy and lysosomal biogenesis. However, the mechanisms by which this occurs have not been elucidated as yet. This investigation aims at dissecting how TFEB is activated and contributes to Tam resistance in luminal A breast cancer cells. TFEB was overexpressed and prominently nuclear in Tam-resistant MCF7 cells (MCF7-TamR) compared with their parental counterpart, and this was not dependent on alterations of its nucleo-cytoplasmic shuttling. Tam promoted the release of lysosomal Ca through the major transient receptor potential cation channel mucolipin subfamily member 1 (TRPML1) and two-pore channels (TPCs), which caused the nuclear translocation and activation of TFEB. Consistently, inhibiting lysosomal calcium release restored the susceptibility of MCF7-TamR cells to Tam. Our findings demonstrate that Tam drives the nuclear relocation and transcriptional activation of TFEB by triggering the release of Ca from the acidic compartment, and they suggest that lysosomal Ca channels may represent new druggable targets to counteract the onset of autophagy-mediated endocrine resistance in luminal A breast cancer cells.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms25010458