Inhibition of proteasome, but not lysosome, upregulates organic anion transporter 3 in vitro and in vivo

Yunzhou Fan, Haoxun Wang, Zhou Yu, Zhengxuan Liang, Yufan Li, Guofeng You

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Organic anion transporter 3 (OAT3), an indispensable basolateral membrane transporter predominantly distributed in the kidney proximal tubules, mediated the systemic clearance of substrates including clinical drugs, nutrients, endogenous and exogenous metabolites, toxins, and critically sustains body homeostasis. Preliminary data in this study showed that classical proteasome inhibitors (e.g., MG132), but not lysosome inhibitors, significantly increased the OAT3 ubiquitination and OAT3-mediated transport of estrone sulfate (ES) in OAT3 stable expressing cells, indicating that proteasome rather than lysosome is involved in the intracellular fate of OAT3. Next, bortezomib and carfilzomib, two FDA-approved and widely applied anticancer agents through selective targeting proteasome, were further used to define the role of inhibiting proteasome in OAT3 regulation and related molecular mechanisms. The results showed that 20S proteasome activity in cell lysates was suppressed with bortezomib and carfilzomib treatment, leading to the increased OAT3 ubiquitination, stimulated transport activity of ES, enhanced OAT3 surface and total expression. The upregulated OAT3 function by proteasome inhibition was attributed to the augment in maximum transport velocity and stability of membrane OAT3. Lastly, in vivo study using Sprague Dawley rats validated that proteasome inhibition using bortezomib induced enhancement of OAT3 ubiquitination and membrane expression in kidney. These data suggest that activity of proteasome but not lysosome could have an impact on the physiological function of OAT3, and proteasome displayed a promising target for OAT3 regulation in vitro and in vivo, and could be used in restoring OAT3 impairment under pathological conditions, avoiding OAT3-associated toxicity and diseases, ensuring drug efficacy and safety.

Original languageEnglish (US)
Article number115387
JournalBiochemical Pharmacology
Volume208
DOIs
StatePublished - Feb 2023

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Pharmacology

Keywords

  • Bortezomib
  • Carfilzomib
  • Lysosome
  • Proteasome
  • Transporter
  • Ubiquitination

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