Next Article in Journal
Voltage Sensing in Bacterial Protein Translocation
Previous Article in Journal
Characterization of Matrix Metalloprotease-9 Gene from Nile tilapia (Oreochromis niloticus) and Its High-Level Expression Induced by the Streptococcus agalactiae Challenge
Open AccessArticle

Lysosomal Fusion: An Efficient Mechanism Increasing Their Sequestration Capacity for Weak Base Drugs without Apparent Lysosomal Biogenesis

Department of Anatomy, Faculty of Medicine and Dentistry, Palacky University Olomouc, Hnevotinska 3, 77515 Olomouc, Czech Republic
*
Author to whom correspondence should be addressed.
Biomolecules 2020, 10(1), 77; https://doi.org/10.3390/biom10010077
Received: 10 October 2019 / Revised: 27 December 2019 / Accepted: 30 December 2019 / Published: 3 January 2020
(This article belongs to the Section Biochemistry)
Lysosomal sequestration of anticancer therapeutics lowers their cytotoxic potential, reduces drug availability at target sites, and contributes to cancer resistance. Only recently has it been shown that lysosomal sequestration of weak base drugs induces lysosomal biogenesis mediated by activation of transcription factor EB (TFEB) which, in turn, enhances their accumulation capacity, thereby increasing resistance to these drugs. Here, we addressed the question of whether lysosomal biogenesis is the only mechanism that increases lysosomal sequestration capacity. We found that lysosomal sequestration of some tyrosine kinase inhibitors (TKIs), gefitinib (GF) and imatinib (IM), induced expansion of the lysosomal compartment. However, an expression analysis of lysosomal genes, including lysosome-associated membrane proteins 1, 2 (LAMP1, LAMP2), vacuolar ATPase subunit B2 (ATP6V1B2), acid phosphatase (ACP), and galactosidase beta (GLB) controlled by TFEB, did not reveal increased expression. Instead, we found that both studied TKIs, GF and IM, induced lysosomal fusion which was dependent on nicotinic acid adenine dinucleotide phosphate (NAADP) mediated Ca2+signaling. A theoretical analysis revealed that lysosomal fusion is sufficient to explain the enlargement of lysosomal sequestration capacity. In conclusion, we demonstrated that extracellular TKIs, GF and IM, induced NAADP/Ca2+ mediated lysosomal fusion, leading to enlargement of the lysosomal compartment with significantly increased sequestration capacity for these drugs without apparent lysosomal biogenesis. View Full-Text
Keywords: tyrosine kinase inhibitors; lysosomal sequestration capacity; lysosomal fusion; K562 cells; Hl-60 cells tyrosine kinase inhibitors; lysosomal sequestration capacity; lysosomal fusion; K562 cells; Hl-60 cells
Show Figures

Graphical abstract

MDPI and ACS Style

Skoupa, N.; Dolezel, P.; Mlejnek, P. Lysosomal Fusion: An Efficient Mechanism Increasing Their Sequestration Capacity for Weak Base Drugs without Apparent Lysosomal Biogenesis. Biomolecules 2020, 10, 77.

Show more citation formats Show less citations formats
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop