Ridinger, Johannes and Koeneke, Emily and Kolbinger, Fiona R. and Koerholz, Katharina and Mahboobi, Siavosh and Hellweg, Lars and Gunkel, Nikolas and Miller, Aubry K. and Peterziel, Heike and Schmezer, Peter and Hamacher-Brady, Anne and Witt, Olaf and Oehme, Ina (2018) Dual role of HDAC10 in lysosomal exocytosis and DNA repair promotes neuroblastoma chemoresistance. SCIENTIFIC REPORTS, 8: 10039. ISSN 2045-2322,
Full text not available from this repository. (Request a copy)Abstract
Drug resistance is a leading cause for treatment failure in many cancers, including neuroblastoma, the most common solid extracranial childhood malignancy. Previous studies from our lab indicate that histone deacetylase 10 (HDAC10) is important for the homeostasis of lysosomes, i.e. acidic vesicular organelles involved in the degradation of various biomolecules. Here, we show that depleting or inhibiting HDAC10 results in accumulation of lysosomes in chemotherapy-resistant neuroblastoma cell lines, as well as in the intracellular accumulation of the weakly basic chemotherapeutic doxorubicin within lysosomes. Interference with HDAC10 does not block doxorubicin efflux from cells via P-glycoprotein inhibition, but rather via inhibition of lysosomal exocytosis. In particular, intracellular doxorubicin does not remain trapped in lysosomes but also accumulates in the nucleus, where it promotes neuroblastoma cell death. Our data suggest that lysosomal exocytosis under doxorubicin treatment is important for cell survival and that inhibition of HDAC10 further induces DNA double-strand breaks (DSBs), providing additional mechanisms that sensitize neuroblastoma cells to doxorubicin. Taken together, we demonstrate that HDAC10 inhibition in combination with doxorubicin kills neuroblastoma, but not non-malignant cells, both by impeding drug efflux and enhancing DNA damage, providing a novel opportunity to target chemotherapy resistance.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | HISTONE DEACETYLASE INHIBITORS; MULTIDRUG-RESISTANCE; DRUG-RESISTANCE; THERAPEUTIC TARGET; EPITHELIAL-CELLS; AUTOPHAGY; CANCER; SEQUESTRATION; DOXORUBICIN; CHEMOTHERAPY; |
| Subjects: | 500 Science > 540 Chemistry & allied sciences |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry I (Prof. Elz) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 19 Feb 2020 09:46 |
| Last Modified: | 19 Feb 2020 09:46 |
| URI: | https://pred.uni-regensburg.de/id/eprint/14264 |
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