Reversine inhibits Colon Carcinoma Cell Migration by Targeting JNK1

Mohamed Jemaà,Ramin Massoumi,Florian Lang,Myriam Fezai,Chamseddine Kifagi,Renée Daams,Yasmin Abassi

doi:10.1038/s41598-018-30251-w

Abstract

Colorectal cancer is one of the most commonly diagnosed cancers and the third most common cause of cancer-related death. Metastasis is the leading reason for the resultant mortality of these patients. Accordingly, development and characterization of novel anti-cancer drugs limiting colorectal tumor cell dissemination and metastasis are needed. In this study, we found that the small molecule Reversine reduces the migration potential of human colon carcinoma cells in vitro. A coupled kinase assay with bio-informatics approach identified the c-Jun N-terminal kinase (JNK) cascade as the main pathway inhibited by Reversine. Knockdown experiments and pharmacological inhibition identified JNK1 but not JNK2, as a downstream effector target in cancer cell migration. Xenograft experiments confirm the effect of JNK inhibition in the metastatic potential of colon cancer cells. These results highlight the impact of individual JNK isoforms in cancer cell metastasis and propose Reversine as a novel anti-cancer molecule for treatment of colon cancer patients.

Highlights

Colorectal cancer (CRC), a tumor on the inner lining of the rectum or colon is one of the most common cancers and a major cause of cancer-related death worldwide[1,2]
We report the identification of the small molecules Reversine and SP600125, which can interfere with Jun N-terminal kinase (JNK) signaling, as inhibitors of migration and metastasis of colon carcinoma cells
We explored the effect of Reversine and SP600125 on the human colon carcinoma RKO cells

Summary

Introduction

Colorectal cancer (CRC), a tumor on the inner lining of the rectum or colon is one of the most common cancers and a major cause of cancer-related death worldwide[1,2]. Two well-known tumor suppressor genes; FBXW7 (F-box/ WD repeat-containing protein 7) and PDCD4 (programmed cell death 4) that can inhibit the activity of JNK, were shown to be inactivated in CRC8–10. Along those lines, pharmacologic inhibition of JNK reduced the growth of several adenocarcinoma cell lines[7,11]. The role of Reversine in anti-tumor activities, including mitotic catastrophe, cell-cycle arrest, polyploidy and autophagy was discovered in several cancer cell lines[23,24,25,26,27]. We identified Reversine as a potent inhibitor of colon cancer cells migration and metastasis.

Methods

Results

Conclusion