Topotecan and Ginkgolic Acid Inhibit the Expression and Transport Activity of Human Organic Anion Transporter 3 by Suppressing SUMOylation of the Transporter
Abstract
:1. Introduction
2. Materials and Methods
2.1. Materials
2.2. Cell Culture and Transfection
2.3. Transport Activity Measurement (Uptake Assay)
2.4. Biotinylation Assay
2.5. Degradation Assay
2.6. Immunoprecipitation
2.7. Cytotoxicity Assay
2.8. SDS-PAGE and Western Blotting
2.9. Data Analysis
3. Results
3.1. Effects of Topotecan and GA on OAT3 SUMOylation
3.2. Effects of Topotecan and GA on OAT3 Transport Activity
3.3. Reversibility of the Effects of Topotecan and GA on OAT3
3.4. Effects of Topotecan and GA on OAT3 Expression
3.5. Effects of Topotecan and GA on OAT3 Stability
3.6. Effects of Topotecan on Ubc9
3.7. Effects of Topotecan on SENP2
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Czuba, L.C.; Hillgren, K.M.; Swaan, P.W. Post-Translational Modifications of Transporters. Pharmacol. Ther. 2018, 192, 88–99. [Google Scholar] [CrossRef] [PubMed]
- Lee, W.; Ha, J.; Sugiyama, Y. Post-Translational Regulation of the Major Drug Transporters in the Families of Organic Anion Transporters and Organic Anion–Transporting Polypeptides. J. Biol. Chem. 2020, 295, 17349–17364. [Google Scholar] [CrossRef] [PubMed]
- Zhang, J.; Wang, H.; Fan, Y.; Yu, Z.; You, G. Regulation of Organic Anion Transporters: Role in Physiology, Pathophysiology, and Drug Elimination. Pharmacol. Ther. 2021, 217, 107647. [Google Scholar] [CrossRef]
- Wang, L.; Sweet, D.H. Interaction of Natural Dietary and Herbal Anionic Compounds and Flavonoids with Human Organic Anion Transporters 1 (SLC22A6), 3 (SLC22A8), and 4 (SLC22A11). Evid.-Based Complement. Altern. Med. 2013, 2013, 612527. [Google Scholar] [CrossRef]
- Yee, S.W.; Giacomini, K.M. Emerging Roles of the Human Solute Carrier 22 Family. Drug Metab. Dispos. 2022, 50, 1193–1210. [Google Scholar] [CrossRef]
- Huo, X.; Liu, K. Renal Organic Anion Transporters in Drug–Drug Interactions and Diseases. Eur. J. Pharm. Sci. 2018, 112, 8–19. [Google Scholar] [CrossRef]
- Chu, X.; Prasad, B.; Neuhoff, S.; Yoshida, K.; Leeder, J.S.; Mukherjee, D.; Taskar, K.; Varma, M.V.S.; Zhang, X.; Yang, X.; et al. Clinical Implications of Altered Drug Transporter Abundance/Function and PBPK Modeling in Specific Populations: An ITC Perspective. Clin. Pharmacol. Ther. 2022, 112, 501–526. [Google Scholar] [CrossRef] [PubMed]
- Zhang, L.; Liu, Q.; Huang, S.-M.; Lionberger, R. Transporters in Regulatory Science: Notable Contributions from Dr. Giacomini in the Past Two Decades. Drug Metab. Dispos. 2022, 50, 1211–1217. [Google Scholar] [CrossRef]
- Liu, X. SLC Family Transporters. In Drug Transporters in Drug Disposition, Effects and Toxicity; Liu, X., Pan, G., Eds.; Advances in Experimental Medicine and Biology; Springer: Singapore, 2019; Volume 1141, pp. 101–202. ISBN 9789811376467. [Google Scholar]
- Giacomini, K.M.; Huang, S.-M. Transporters in Drug Development and Clinical Pharmacology. Clin. Pharmacol. Ther. 2013, 94, 3–9. [Google Scholar] [CrossRef]
- Yu, Z.; Liu, C.; Zhang, J.; Liang, Z.; You, G. Protein Kinase C Regulates Organic Anion Transporter 1 through Phosphorylating Ubiquitin Ligase Nedd4–2. BMC Mol. Cell Biol. 2021, 22, 53. [Google Scholar] [CrossRef]
- Fan, Y.; Wang, H.; Yu, Z.; Liang, Z.; Li, Y.; You, G. Inhibition of Proteasome, but Not Lysosome, Upregulates Organic Anion Transporter 3 In Vitro and In Vivo. Biochem. Pharmacol. 2023, 208, 115387. [Google Scholar] [CrossRef]
- Wang, H.; Zhang, J.; You, G. Activation of Protein Kinase A Stimulates SUMOylation, Expression, and Transport Activity of Organic Anion Transporter 3. AAPS J. 2019, 21, 30. [Google Scholar] [CrossRef] [PubMed]
- Zhang, J.; Yu, Z.; You, G. Insulin-like Growth Factor 1 Modulates the Phosphorylation, Expression, and Activity of Organic Anion Transporter 3 through Protein Kinase A Signaling Pathway. Acta Pharm. Sin. B 2020, 10, 186–194. [Google Scholar] [CrossRef]
- Yu, Z.; Zhang, J.; Liang, Z.; Wu, J.; Liu, K.; You, G. Pancreatic Hormone Insulin Modulates Organic Anion Transporter 1 in the Kidney: Regulation via Remote Sensing and Signaling Network. AAPS J. 2023, 25, 13. [Google Scholar] [CrossRef]
- Yu, Z.; Wang, H.; You, G. The Regulation of Human Organic Anion Transporter 4 by Insulin-like Growth Factor 1 and Protein Kinase B Signaling. Biochem. Pharmacol. 2023, 215, 115702. [Google Scholar] [CrossRef] [PubMed]
- Foran, E.; Rosenblum, L.; Bogush, A.; Pasinelli, P.; Trotti, D. Sumoylation of the Astroglial Glutamate Transporter EAAT2 Governs Its Intracellular Compartmentalization: Sumoylation of EAAT2. Glia 2014, 62, 1241–1253. [Google Scholar] [CrossRef] [PubMed]
- Kho, C.; Lee, A.; Jeong, D.; Oh, J.G.; Gorski, P.A.; Fish, K.; Sanchez, R.; DeVita, R.J.; Christensen, G.; Dahl, R.; et al. Small-Molecule Activation of SERCA2a SUMOylation for the Treatment of Heart Failure. Nat. Commun. 2015, 6, 7229. [Google Scholar] [CrossRef]
- Yang, Y.; He, Y.; Wang, X.; Liang, Z.; He, G.; Zhang, P.; Zhu, H.; Xu, N.; Liang, S. Protein SUMOylation Modification and Its Associations with Disease. Open Biol. 2017, 7, 170167. [Google Scholar] [CrossRef]
- Hu, X.; Liu, Z.; Duan, X.; Han, X.; Yuan, M.; Liu, L.; Xia, X.; Li, N.; Qin, J.; Wang, Y. Blocking MCT4 SUMOylation Inhibits the Growth of Breast Cancer Cells. Mol. Carcinog. 2021, 60, 702–714. [Google Scholar] [CrossRef]
- Saitoh, H.; Hinchey, J. Functional Heterogeneity of Small Ubiquitin-Related Protein Modifiers SUMO-1 versus SUMO-2/3. J. Biol. Chem. 2000, 275, 6252–6258. [Google Scholar] [CrossRef]
- Hickey, C.M.; Wilson, N.R.; Hochstrasser, M. Function and Regulation of SUMO Proteases. Nat. Rev. Mol. Cell Biol. 2012, 13, 755–766. [Google Scholar] [CrossRef] [PubMed]
- Enserink, J.M. Sumo and the Cellular Stress Response. Cell Div. 2015, 10, 4. [Google Scholar] [CrossRef] [PubMed]
- Chang, H.-M.; Yeh, E.T.H. SUMO: From Bench to Bedside. Physiol. Rev. 2020, 100, 1599–1619. [Google Scholar] [CrossRef]
- Van Warmerdam, L.J.C.; Verweij, J.; Schellens, J.H.M.; Rosing, H.; Davies, B.E.; De Boer-Dennert, M.; Maes, R.A.A.; Beijnen, J.H. Pharmacokinetics and Pharmacodynamics of Topotecan Administered Daily for 5 Days Every 3 Weeks. Cancer Chemother. Pharmacol. 1995, 35, 237–245. [Google Scholar] [CrossRef] [PubMed]
- Kollmannsberger, C.; Mross, K.; Jakob, A.; Kanz, L.; Bokemeyer, C. Topotecan—A Novel Topoisomerase I Inhibitor: Pharmacology and Clinical Experience. Oncology 1999, 56, 1–12. [Google Scholar] [CrossRef]
- Matsumoto, S.; Yoshida, K.; Ishiguro, N.; Maeda, T.; Tamai, I. Involvement of Rat and Human Organic Anion Transporter 3 in the Renal Tubular Secretion of Topotecan [(S)-9-Dimethylaminomethyl-10-Hydroxy-Camptothecin Hydrochloride]. J. Pharmacol. Exp. Ther. 2007, 322, 1246–1252. [Google Scholar] [CrossRef] [PubMed]
- Mo, Y.-Y.; Yu, Y.; Shen, Z.; Beck, W.T. Nucleolar Delocalization of Human Topoisomerase I in Response to Topotecan Correlates with Sumoylation of the Protein. J. Biol. Chem. 2002, 277, 2958–2964. [Google Scholar] [CrossRef]
- Bernstock, J.D.; Ye, D.; Gessler, F.A.; Lee, Y.; Peruzzotti-Jametti, L.; Baumgarten, P.; Johnson, K.R.; Maric, D.; Yang, W.; Kögel, D.; et al. Topotecan Is a Potent Inhibitor of SUMOylation in Glioblastoma Multiforme and Alters Both Cellular Replication and Metabolic Programming. Sci. Rep. 2017, 7, 7425. [Google Scholar] [CrossRef] [PubMed]
- Liu, X.; Heras, G.; Lauschke, V.M.; Mi, J.; Tian, G.; Gastaldello, S. High Glucose-Induced Oxidative Stress Accelerates Myogenesis by Altering SUMO Reactions. Exp. Cell Res. 2020, 395, 112234. [Google Scholar] [CrossRef]
- Wang, X.; Oates, J.C.; Helke, K.L.; Gilkeson, G.S.; Zhang, X.K. Camptothecin and Topotecan, Inhibitors of Transcription Factor Fli-1 and Topoisomerase, Markedly Ameliorate Lupus Nephritis in (NZB × NZW)F1 Mice and Reduce the Production of Inflammatory Mediators in Human Renal Cells. Arthritis Rheumatol. 2021, 73, 1478–1488. [Google Scholar] [CrossRef]
- Sinha, B.K.; Tokar, E.J.; Bushel, P.R. Elucidation of Mechanisms of Topotecan-Induced Cell Death in Human Breast MCF-7 Cancer Cells by Gene Expression Analysis. Front. Genet. 2020, 11, 775. [Google Scholar] [CrossRef] [PubMed]
- Fukuda, I.; Ito, A.; Hirai, G.; Nishimura, S.; Kawasaki, H.; Saitoh, H.; Kimura, K.; Sodeoka, M.; Yoshida, M. Ginkgolic Acid Inhibits Protein SUMOylation by Blocking Formation of the E1-SUMO Intermediate. Chem. Biol. 2009, 16, 133–140. [Google Scholar] [CrossRef] [PubMed]
- Ude, C.; Schubert-Zsilavecz, M.; Wurglics, M. Ginkgo Biloba Extracts: A Review of the Pharmacokinetics of the Active Ingredients. Clin. Pharmacokinet. 2013, 52, 727–749. [Google Scholar] [CrossRef]
- Guo, C.; Wei, Q.; Su, Y.; Dong, Z. SUMOylation Occurs in Acute Kidney Injury and Plays a Cytoprotective Role. Biochim. Biophys. Acta (BBA)—Mol. Basis Dis. 2015, 1852, 482–489. [Google Scholar] [CrossRef] [PubMed]
- Jedeszko, C.; Paez-Ribes, M.; Di Desidero, T.; Man, S.; Lee, C.R.; Xu, P.; Bjarnason, G.A.; Bocci, G.; Kerbel, R.S. Postsurgical Adjuvant or Metastatic Renal Cell Carcinoma Therapy Models Reveal Potent Antitumor Activity of Metronomic Oral Topotecan with Pazopanib. Sci. Transl. Med. 2015, 7, 282ra50. [Google Scholar] [CrossRef]
- Qian, Y.; Su, S.; Wei, M.; Zhu, Z.; Guo, S.; Yan, H.; Tao, J.; Qian, D.; Duan, J. Interactions of Pharmacokinetic Profiles of Ginkgotoxin and Ginkgolic Acids in Rat Plasma after Oral Administration. J. Pharm. Biomed. Anal. 2019, 163, 88–94. [Google Scholar] [CrossRef] [PubMed]
- Duan, P.; Li, S.; You, G. Angiotensin II Inhibits Activity of Human Organic Anion Transporter 3 through Activation of Protein Kinase Cα: Accelerating Endocytosis of the Transporter. Eur. J. Pharmacol. 2010, 627, 49–55. [Google Scholar] [CrossRef]
- Takeda, M.; Narikawa, S.; Hosoyamada, M.; Ho Cha, S.; Sekine, T.; Endou, H. Characterization of Organic Anion Transport Inhibitors Using Cells Stably Expressing Human Organic Anion Transporters. Eur. J. Pharmacol. 2001, 419, 113–120. [Google Scholar] [CrossRef] [PubMed]
- Smith, S.M.; Wunder, M.B.; Norris, D.A.; Shellman, Y.G. A Simple Protocol for Using a LDH-Based Cytotoxicity Assay to Assess the Effects of Death and Growth Inhibition at the Same Time. PLoS ONE 2011, 6, e26908. [Google Scholar] [CrossRef]
- Kim, Y.S.; Keyser, S.G.L.; Schneekloth, J.S. Synthesis of 2′,3′,4′-Trihydroxyflavone (2-D08), an Inhibitor of Protein Sumoylation. Bioorganic Med. Chem. Lett. 2014, 24, 1094–1097. [Google Scholar] [CrossRef]
- Kim, Y.S.; Nagy, K.; Keyser, S.; Schneekloth, J.S. An Electrophoretic Mobility Shift Assay Identifies a Mechanistically Unique Inhibitor of Protein Sumoylation. Chem. Biol. 2013, 20, 604–613. [Google Scholar] [CrossRef] [PubMed]
- Cartier, E.; Garcia-Olivares, J.; Janezic, E.; Viana, J.; Moore, M.; Lin, M.L.; Caplan, J.L.; Torres, G.; Kim, Y.-H. The SUMO-Conjugase Ubc9 Prevents the Degradation of the Dopamine Transporter, Enhancing Its Cell Surface Level and Dopamine Uptake. Front. Cell. Neurosci. 2019, 13, 35. [Google Scholar] [CrossRef] [PubMed]
- Wang, H.; You, G. The SUMO-Specific Protease Senp2 Regulates SUMOylation, Expression and Function of Human Organic Anion Transporter 3. Biochim. Biophys. Acta (BBA)—Biomembr. 2019, 1861, 1293–1301. [Google Scholar] [CrossRef] [PubMed]
- Hua, D.; Wu, X. Small-Molecule Inhibitors Targeting Small Ubiquitin-like Modifier Pathway for the Treatment of Cancers and Other Diseases. Eur. J. Med. Chem. 2022, 233, 114227. [Google Scholar] [CrossRef] [PubMed]
- Tokarz, P.; Woźniak, K. SENP Proteases as Potential Targets for Cancer Therapy. Cancers 2021, 13, 2059. [Google Scholar] [CrossRef] [PubMed]
- Molfetta, R.; Petillo, S.; Cippitelli, M.; Paolini, R. SUMOylation and Related Post-Translational Modifications in Natural Killer Cell Anti-Cancer Responses. Front. Cell Dev. Biol. 2023, 11, 1213114. [Google Scholar] [CrossRef]
- Kroonen, J.S.; Vertegaal, A.C.O. Targeting SUMO Signaling to Wrestle Cancer. Trends Cancer 2021, 7, 496–510. [Google Scholar] [CrossRef] [PubMed]
- He, X.; Riceberg, J.; Soucy, T.; Koenig, E.; Minissale, J.; Gallery, M.; Bernard, H.; Yang, X.; Liao, H.; Rabino, C.; et al. Probing the Roles of SUMOylation in Cancer Cell Biology by Using a Selective SAE Inhibitor. Nat. Chem. Biol. 2017, 13, 1164–1171. [Google Scholar] [CrossRef] [PubMed]
- Zhou, J.; Cui, S.; He, Q.; Guo, Y.; Pan, X.; Zhang, P.; Huang, N.; Ge, C.; Wang, G.; Gonzalez, F.J.; et al. SUMOylation Inhibitors Synergize with FXR Agonists in Combating Liver Fibrosis. Nat. Commun. 2020, 11, 240. [Google Scholar] [CrossRef]
- Fukuda, I.; Ito, A.; Uramoto, M.; Saitoh, H.; Kawasaki, H.; Osada, H.; Yoshida, M. Kerriamycin B Inhibits Protein SUMOylation. J. Antibiot. 2009, 62, 221–224. [Google Scholar] [CrossRef]
- Suzawa, M.; Miranda, D.A.; Ramos, K.A.; Ang, K.K.-H.; Faivre, E.J.; Wilson, C.G.; Caboni, L.; Arkin, M.R.; Kim, Y.-S.; Fletterick, R.J.; et al. A Gene-Expression Screen Identifies a Non-Toxic Sumoylation Inhibitor That Mimics SUMO-Less Human LRH-1 in Liver. eLife 2015, 4, e09003. [Google Scholar] [CrossRef] [PubMed]
- Langston, S.P.; Grossman, S.; England, D.; Afroze, R.; Bence, N.; Bowman, D.; Bump, N.; Chau, R.; Chuang, B.-C.; Claiborne, C.; et al. Discovery of TAK-981, a First-in-Class Inhibitor of SUMO-Activating Enzyme for the Treatment of Cancer. J. Med. Chem. 2021, 64, 2501–2520. [Google Scholar] [CrossRef]
- Kumar, S.; Schoonderwoerd, M.J.A.; Kroonen, J.S.; De Graaf, I.J.; Sluijter, M.; Ruano, D.; González-Prieto, R.; Verlaan-de Vries, M.; Rip, J.; Arens, R.; et al. Targeting Pancreatic Cancer by TAK-981: A SUMOylation Inhibitor That Activates the Immune System and Blocks Cancer Cell Cycle Progression in a Preclinical Model. Gut 2022, 71, 2266–2283. [Google Scholar] [CrossRef] [PubMed]
- Lightcap, E.S.; Yu, P.; Grossman, S.; Song, K.; Khattar, M.; Xega, K.; He, X.; Gavin, J.M.; Imaichi, H.; Garnsey, J.J.; et al. A Small-Molecule SUMOylation Inhibitor Activates Antitumor Immune Responses and Potentiates Immune Therapies in Preclinical Models. Sci. Transl. Med. 2021, 13, eaba7791. [Google Scholar] [CrossRef] [PubMed]
- Hirohama, M.; Kumar, A.; Fukuda, I.; Matsuoka, S.; Igarashi, Y.; Saitoh, H.; Takagi, M.; Shin-ya, K.; Honda, K.; Kondoh, Y.; et al. Spectomycin B1 as a Novel SUMOylation Inhibitor That Directly Binds to SUMO E2. ACS Chem. Biol. 2013, 8, 2635–2642. [Google Scholar] [CrossRef] [PubMed]
- Huang, W.; He, T.; Chai, C.; Yang, Y.; Zheng, Y.; Zhou, P.; Qiao, X.; Zhang, B.; Liu, Z.; Wang, J.; et al. Triptolide Inhibits the Proliferation of Prostate Cancer Cells and Down-Regulates SUMO-Specific Protease 1 Expression. PLoS ONE 2012, 7, e37693. [Google Scholar] [CrossRef] [PubMed]
- Wu, J.; Lei, H.; Zhang, J.; Chen, X.; Tang, C.; Wang, W.; Xu, H.; Xiao, W.; Gu, W.; Wu, Y. Momordin Ic, a New Natural SENP1 Inhibitor, Inhibits Prostate Cancer Cell Proliferation. Oncotarget 2016, 7, 58995–59005. [Google Scholar] [CrossRef] [PubMed]
- Ambaye, N.; Chen, C.-H.; Khanna, S.; Li, Y.-J.; Chen, Y. Streptonigrin Inhibits SENP1 and Reduces the Protein Level of Hypoxia-Inducible Factor 1α (HIF1α) in Cells. Biochemistry 2018, 57, 1807–1813. [Google Scholar] [CrossRef]
- Zhang, Y.; Wei, H.; Zhou, Y.; Li, Z.; Gou, W.; Meng, Y.; Zheng, W.; Li, J.; Li, Y.; Zhu, W. Identification of Potent SENP1 Inhibitors That Inactivate SENP1/JAK2/STAT Signaling Pathway and Overcome Platinum Drug Resistance in Ovarian Cancer. Clin. Transl. Med. 2021, 11, e649. [Google Scholar] [CrossRef]
- Chang, C.-C.; Tung, C.-H.; Chen, C.-W.; Tu, C.-H.; Chu, Y.-W. SUMOgo: Prediction of Sumoylation Sites on Lysines by Motif Screening Models and the Effects of Various Post-Translational Modifications. Sci. Rep. 2018, 8, 15512. [Google Scholar] [CrossRef]
- Matic, I.; Schimmel, J.; Hendriks, I.A.; van Santen, M.A.; van de Rijke, F.; van Dam, H.; Gnad, F.; Mann, M.; Vertegaal, A.C.O. Site-Specific Identification of SUMO-2 Targets in Cells Reveals an Inverted SUMOylation Motif and a Hydrophobic Cluster SUMOylation Motif. Mol. Cell 2010, 39, 641–652. [Google Scholar] [CrossRef] [PubMed]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Yu, Z.; You, G. Topotecan and Ginkgolic Acid Inhibit the Expression and Transport Activity of Human Organic Anion Transporter 3 by Suppressing SUMOylation of the Transporter. Pharmaceutics 2024, 16, 638. https://doi.org/10.3390/pharmaceutics16050638
Yu Z, You G. Topotecan and Ginkgolic Acid Inhibit the Expression and Transport Activity of Human Organic Anion Transporter 3 by Suppressing SUMOylation of the Transporter. Pharmaceutics. 2024; 16(5):638. https://doi.org/10.3390/pharmaceutics16050638
Chicago/Turabian StyleYu, Zhou, and Guofeng You. 2024. "Topotecan and Ginkgolic Acid Inhibit the Expression and Transport Activity of Human Organic Anion Transporter 3 by Suppressing SUMOylation of the Transporter" Pharmaceutics 16, no. 5: 638. https://doi.org/10.3390/pharmaceutics16050638