| Autor: |
Harshit Shah, Metodi Stankov, Diana Panayotova-Dimitrova, Amir Yazdi, Ramachandramouli Budida, Jan-Henning Klusmann, Georg M. N. Behrens |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
|
| Zdroj: |
Frontiers in Oncology, Vol 13 (2023) |
| Druh dokumentu: |
article |
| ISSN: |
2234-943X |
| DOI: |
10.3389/fonc.2023.999738 |
| Popis: |
IntroductionCurrent cancer research has led to a renewed interest in exploring lysosomal membrane permeabilization and lysosomal cell death as a targeted therapeutic approach for cancer treatment. Evidence suggests that differences in lysosomal biogenesis between cancer and normal cells might open a therapeutic window. Lysosomal membrane stability may be affected by the so-called ‘busy lysosomal behaviour’ characterized by higher lysosomal abundance and activity and more intensive fusion or interaction with other vacuole compartments.MethodsWe used a panel of multiple myeloid leukemia (ML) cell lines as well as leukemic patient samples and updated methodology to study auto-lysosomal compartment, lysosomal membrane permeabilization and lysosomal cell death.ResultsOur analyses demonstrated several-fold higher constitutive autolysosomal activity in ML cells as compared to human CD34+ hematopoietic cells. Importantly, we identified mefloquine as a selective activator of ML cells' lysosomal biogenesis, which induced a sizeable increase in ML lysosomal mass, acidity as well as cathepsin B and L activity. Concomitant mTOR inhibition synergistically increased lysosomal activity and autolysosomal fusion and simultaneously decreased the levels of key lysosomal stabilizing proteins, such as LAMP-1 and 2.DiscussionIn conclusion, mefloquine treatment combined with mTOR inhibition synergistically induced targeted ML cell death without additional toxicity. Taken together, these data provide a molecular mechanism and thus a rationale for a therapeutic approach for specific targeting of ML lysosomes. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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