Cancer-Type Organic Anion Transporting Polypeptide 1B3 Is Localized in Lysosomes and Mediates Resistance against Kinase Inhibitors

Haberkorn B, Oswald S, Kehl N, Geßner A, Taudte V, Dobert J, Zunke F, Fromm M, König J (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Molecular Pharmacology American Society for Pharmacology and Experimental Therapeutics (ASPET)

Book Volume: 102

Pages Range: 248-258

Journal Issue: 6

DOI: 10.1124/molpharm.122.000539

Abstract

Cancer-type organic anion transporting polypeptide 1B3 (CtOATP1B3), a splice variant of the hepatic uptake transporter OATP1B3 (liver-type), is expressed in several tumor entities, including colorectal carcinoma (CRC) and breast cancer. In CRC, high OATP1B3 expression has been associated with reduced progression-free and overall survival. Several kinase inhibitors used for antitumor treatment are substrates and/or inhibitors of OATP1B3 (e.g., encorafenib, vemurafenib). The functional importance of CtOATP1B3 has not been elucidated so far. Human embryonic kidney 293 cells stably overexpressing Ct-OATP1B3 protein were established and compared with control cells. Confocal laser scanning microscopy, immunoblot, and proteomics-based expression analysis demonstrated that Ct-OATP1B3 protein is intracellularly localized in lysosomes of stably transfected cells. Cytotoxicity experiments showed that cells recombinantly expressing the Ct-OATP1B3 protein were more resistant against the kinase inhibitor encorafenib compared with control cells [e.g., encorafenib (100 mM) survival rates: 89.5% versus 52.8%]. In line with these findings, colorectal cancer DLD1 cells endogenously expressing Ct-OATP1B3 protein had poorer survival rates when the OATP1B3 substrate bromosulfophthalein (BSP) was coincubated with encorafenib or vemurafenib compared with the incubation with the kinase inhibitor alone. This indicates a competitive inhibition of Ct-OATP1B3–mediated uptake into lysosomes by BSP. Accordingly, mass spectrometry-based drug analysis of lysosomes showed a reduced lysosomal accumulation of encorafenib in DLD1 cells additionally exposed to BSP. These results demonstrate that Ct-OATP1B3 protein is localized in the lysosomal membrane and can mediate transport of certain kinase inhibitors into lysosomes, revealing a new mechanism of resistance.

Authors with CRIS profile

Bastian Haberkorn Lehrstuhl für Klinische Pharmakologie und Klinische Toxikologie Niklas Kehl Lehrstuhl für Klinische Pharmakologie und Klinische Toxikologie Arne Geßner Lehrstuhl für Klinische Pharmakologie und Klinische Toxikologie Verena Taudte Lehrstuhl für Klinische Pharmakologie und Klinische Toxikologie Jan Dobert Department of Molecular Neurology Friederike Zunke Juniorprofessur für Translationale Neurowissenschaften Martin Fromm Lehrstuhl für Klinische Pharmakologie und Klinische Toxikologie Jörg König Lehrstuhl für Klinische Pharmakologie und Klinische Toxikologie

Involved external institutions

Universitätsmedizin Rostock DE Germany (DE)

How to cite

APA:

Haberkorn, B., Oswald, S., Kehl, N., Geßner, A., Taudte, V., Dobert, J.,... König, J. (2022). Cancer-Type Organic Anion Transporting Polypeptide 1B3 Is Localized in Lysosomes and Mediates Resistance against Kinase Inhibitors. Molecular Pharmacology, 102(6), 248-258. https://doi.org/10.1124/molpharm.122.000539

MLA:

Haberkorn, Bastian, et al. "Cancer-Type Organic Anion Transporting Polypeptide 1B3 Is Localized in Lysosomes and Mediates Resistance against Kinase Inhibitors." Molecular Pharmacology 102.6 (2022): 248-258.

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