Preclinical evidence that MNK/eIF4E inhibition by cercosporamide enhances the response to antiangiogenic TKI and mTOR inhibitor in renal cell carcinoma.

Abstract

Eukaryotic translation initiation factor 4E (eIF4E) is deregulated in patients with renal cell carcinoma (RCC) and associated with poor prognosis, and is activated and regulated by Mnk kinases. In this study, we investigated the anti-RCC potential of a unique Mnk inhibitor cercosporamide. We showed that cercosporamide is active against RCC cells via suppressing growth, survival and migration. Combination indices value indicated that the combination of cercosporamide with sunitinib or temsirolimus are synergistic in RCC. In two independent RCC xenograft mouse models, complete tumor growth arrest or reverse was observed throughout the duration of drug treatment in the combination of cercosporamide with sunitinib or temsirolimus groups. Of note, cercosporamide inhibited RCC angiogenesis via negatively regulating a number of RCC endothelial cellular events including morphogenesis, migration, growth and survival. Mechanistically, we found that cercosporamide suppressed pro-angiogenic factors VEGF and HIFα, inhibited EMT and reduced pro-survival and cell cycle proteins; and furthermore this was attributed to cercosporamide's ability in inhibiting eIF4E. This work demonstrates the anti-RCC activity of cercosporamide through targeting both RCC tumor cells and angiogenesis, and provides the first preclinical proof-of-concept of evidence of Mnk inhibition for RCC treatment.

• Authors: Sen Chen, Long Cui, Qiao Hu, Yingying Shen, Yan Jiang, Juan Zhao
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 530 Issue 1 Pg. 142-148 (09 10 2020) ISSN: 1090-2104 [Electronic] United States
• PMID: 32828276 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Angiogenesis Inhibitors
• Antineoplastic Agents
• Benzofurans
• Eukaryotic Initiation Factor-4E
• Intracellular Signaling Peptides and Proteins
• Protein Kinase Inhibitors
• cercosporamide
• temsirolimus
• MKNK1 protein, human
• MKNK2 protein, human
• Protein Serine-Threonine Kinases
• TOR Serine-Threonine Kinases
• Sunitinib
• Sirolimus

Topics

• Angiogenesis Inhibitors (pharmacology, therapeutic use)
• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Benzofurans (pharmacology, therapeutic use)
• Carcinoma, Renal Cell (drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Drug Synergism
• Eukaryotic Initiation Factor-4E (antagonists & inhibitors, metabolism)
• Humans
• Intracellular Signaling Peptides and Proteins (antagonists & inhibitors, metabolism)
• Kidney Neoplasms (drug therapy, metabolism, pathology)
• Mice, SCID
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Sirolimus (analogs & derivatives, pharmacology, therapeutic use)
• Sunitinib (pharmacology, therapeutic use)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, metabolism)