CTSB Nuclear Translocation Facilitates DNA Damage and Lysosomal Stress to Promote Retinoblastoma Cell Death.

Publisher: Springer Country of Publication: Switzerland NLM ID: 9423533 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1559-0305 (Electronic) Linking ISSN: 10736085 NLM ISO Abbreviation: Mol Biotechnol Subsets: MEDLINE

Publication: [Cham] : Springer
Original Publication: Totowa, NJ : Humana Press, c1994-

DNA Damage* ; Retinoblastoma*/metabolism ; Retinoblastoma*/genetics ; Retinoblastoma*/pathology ; Lysosomes*/metabolism ; Cathepsin B*/metabolism ; Cathepsin B*/genetics ; Mice, Nude* ; Autophagy*; Animals ; Humans ; Mice ; Cell Line, Tumor ; Cell Nucleus/metabolism ; STAT3 Transcription Factor/metabolism ; STAT3 Transcription Factor/genetics ; BRCA1 Protein/metabolism ; BRCA1 Protein/genetics ; Cell Proliferation ; Cell Cycle Checkpoints ; Apoptosis ; Membrane Proteins/metabolism ; Membrane Proteins/genetics ; Signal Transduction ; Female

Retinoblastoma (RB) is a pernicious tumor originating from photoreceptor precursor cells that often endangers the lives of children. The purpose of our study was to further investigate the influence of cathepsin B (CTSB) nuclear translocation on RB cell death. Y79 cells were injected into the vitreous cavity of nude mice at a dose of 4 µL/mouse to establish an animal model of RB. Real-time quantitative polymerase chain reaction (RT-qPCR), Western blot analysis, a comet assay, a Cell Counting Kit-8 (CCK-8) assay and flow cytometry were used to measure the levels of the interrelated genes and proteins and to evaluate alterations in autophagy, apoptosis, proliferation, DNA damage and cell cycle arrest. CTSB was found to be expressed at low levels in RB animal model samples and RB cell lines. Functionally, CTSB nuclear translocation promoted DNA damage, cell cycle arrest, ferroptosis and autophagy in Y79 cells and inhibited their proliferation. Downstream mechanistic studies showed that nuclear translocation of CTSB facilitates DNA damage and cell cycle arrest in RB cells by inhibiting breast cancer 1 protein (BRCA1) expression and also activates the signal transducer and activator of transcription 3/stimulator of interferon response cGAMP interactor 1 (STAT3/STING1) pathway to induce lysosomal stress, leading to ferroptosis and autophagy in Y79 cells and alleviating RB. Nuclear translocation of CTSB facilitates DNA damage and cell cycle arrest in RB cells by inhibiting BRCA1 expression and activating the STAT3/STING1 pathway and induces lysosomal stress, which eventually leads to ferroptosis and autophagy and mitigates RB.
(© 2023. The Author(s).)

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Keywords: Autophagy; CTSB nuclear translocation; DNA damage repair; Ferroptosis; Lysosomal stress; Retinoblastoma

EC 3.4.22.1 (Cathepsin B)
0 (STAT3 Transcription Factor)
0 (BRCA1 Protein)
EC 3.4.22.1 (CTSB protein, human)
0 (Membrane Proteins)
0 (BRCA1 protein, human)

Date Created: 20231230 Date Completed: 20240925 Latest Revision: 20240928

20250114

PMC11424708

10.1007/s12033-023-01042-0

38159170