Proteasome Inhibitors Bortezomib and Carfilzomib Stimulate the Transport Activity of Human Organic Anion Transporter 1

Abstract

Organic anion transporter 1 (OAT1), expressed at the basolateral membrane of renal proximal tubule epithelial cells, mediates the renal excretion of many clinically important drugs. Previous study in our lab demonstrated that ubiquitin conjugation to OAT1 leads to OAT1 internalization from the cell surface and subsequent degradation. The current study showed that the ubiquitinated OAT1 accumulated in the presence of the proteasomal inhibitors MG132 and ALLN rather than the lysosomal inhibitors leupeptin and pepstatin A, suggesting that ubiquitinated OAT1 degrades through proteasomes. Anticancer drugs bortezomib and carfilzomib target the ubiquitin-proteasome pathway. We therefore investigate the roles of bortezomib and carfilzomib in reversing the ubiquitination-induced downregulation of OAT1 expression and transport activity. We showed that bortezomib and carfilzomib extremely increased the ubiquitinated OAT1, which correlated well with an enhanced OAT1-mediated transport of p-aminohippuric acid and an enhanced OAT1 surface expression. The augmented OAT1 expression and transport activity following the treatment with bortezomib and carfilzomib resulted from a reduced rate of OAT1 degradation. Consistent with this, we found decreased 20S proteasomal activity in cells that were exposed to bortezomib and carfilzomib. In conclusion, this study identified the pathway in which ubiquitinated OAT1 degrades and unveiled a novel role of anticancer drugs bortezomib and carfilzomib in their regulation of OAT1 expression and transport activity.

Solute carrier transporter superfamily member SLC16A1 is a potential prognostic biomarker and associated with immune infiltration in skin cutaneous melanoma

“…The co-expression pattern of SLC16A1 also provides new insights into the treatment of melanoma, that is, inhibiting excessive growth of tumor cells by targeted ubiquitination. Two proteasome inhibitors, bortezomib (Velcade) and carfilzomib (Kyprolis) have been approved by the U.S. Food and Drug Administration [ 32 ]. The ubiquitin inhibitors of P53 and NF-κB are under evaluation in clinical trials [ 33 ].…”

Post-translational regulation of the major drug transporters in the families of organic anion transporters and organic anion–transporting polypeptides

“…In a recent study, the two clinically used proteasome inhibitor drugs (bortezomib and carfilzomib) increased the cellular levels of the ubiquitinated OAT1 protein and also enhanced the level of the functional OAT1 at the plasma membrane (87). Interestingly, the ubiquitinated OAT1 protein displayed the molecular size much higher than expected for a monomer (to the extent much higher than poly-or multi-ubiquitination).…”

The Role of Solute Carrier Transporters in Efficient Anticancer Drug Delivery and Therapy

“…Alam et al (2017) determined the ubiquitination of OATP1B1 and OATP1B3, one of the major mechanisms through which proteins are degraded intracellularly, and the apparent substrate-dependent inhibitory effect of proteosome inhibitor bortezomib, a drug used for multiple myeloma treatment, on OATP1B3-mediated transport [ 245 ]. In another study, treatment with proteasome inhibitors bortezomib and carfilzomib increased the cellular levels of the ubiquitinated OAT1 protein and augmented the functional OAT1 levels at the plasma membrane [ 246 ]. Proteasome inhibitor therapy is often administered for an extended time in combination with other anticancer drugs to suppress the disease’s progression.…”