| Autor: |
Boretto C; Department of Clinical and Biological Sciences, University of Turin, 10125 Turin, Italy., Actis C; Department of Clinical and Biological Sciences, University of Turin, 10125 Turin, Italy., Faris P; Department of Brain and Behavioral Sciences, University of Pavia, 27100 Pavia, Italy., Cordero F; Department of Computer Science, University of Turin, 10149 Turin, Italy., Beccuti M; Department of Computer Science, University of Turin, 10149 Turin, Italy., Ferrero G; Department of Clinical and Biological Sciences, University of Turin, 10125 Turin, Italy., Muzio G; Department of Clinical and Biological Sciences, University of Turin, 10125 Turin, Italy., Moccia F; Laboratory of General Physiology, Department of Biology and Biotechnology 'L. Spallanzani', University of Pavia, 27100 Pavia, Italy., Autelli R; Department of Clinical and Biological Sciences, University of Turin, 10125 Turin, Italy. |
| Abstrakt: |
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 2+ 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 2+ from the acidic compartment, and they suggest that lysosomal Ca 2+ channels may represent new druggable targets to counteract the onset of autophagy-mediated endocrine resistance in luminal A breast cancer cells. |
