Microtubule-targeting agents impair kinesin-2-dependent nuclear transport of β-catenin: Evidence of inhibition of Wnt/β-catenin signaling as an important antitumor mechanism of microtubule-targeting agents.

Abstract

An aberrant accumulation of nuclear β-catenin is closely associated with the augmentation of cancer malignancy. In this work, we report that several microtubule-targeting agents (MTAs) such as vinblastine, taxol, and C12 (combretastatin-2-aminoimidazole analog) inhibit Wnt/β-catenin signaling in oral squamous cell carcinoma (OSCC). We showed that the inhibition of microtubule dynamics by MTAs decreased the level of β-catenin by increasing Axin and adenomatous polyposis coli levels and reducing the level of dishevelled. Furthermore, MTAs strongly reduced the localization of β-catenin in the nucleus. The reduction in the level of nuclear β-catenin was neither due to the degradation of β-catenin in the nucleus nor due to an increase in the export of nuclear β-catenin from the nucleus. A motor protein kinesin-2 was found to assist the nuclear transportation of β-catenin. Interestingly, Wnt/β-catenin signaling antagonist treatment synergized with MTAs and the activators of Wnt/β-catenin signaling antagonized with the MTAs. C12 potently suppressed the growth of 4-Nitroquinoline 1-oxide-induced OSCC in the tongue of C57 black 6 mice and also abrogated Wnt/β-catenin signaling pathway in the tumor. Our results provide evidence that the decrease in Wnt/β-catenin signaling is an important antitumor effect of MTAs and the combined use of MTAs with Wnt/β-catenin signaling antagonists could be a promising strategy for cancer chemotherapy.

• Authors: Anuradha Kumari, Omprakash Shriwas, Shailendra Sisodiya, Manas K Santra, Sankar K Guchhait, Rupesh Dash, Dulal Panda
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 35 Issue 4 Pg. e21539 (04 2021) ISSN: 1530-6860 [Electronic] United States
• PMID: 33742719 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 Federation of American Societies for Experimental Biology.

Chemical References

• beta Catenin

Topics

• Active Transport, Cell Nucleus (physiology)
• Animals
• Carcinoma, Squamous Cell (metabolism)
• Cell Line, Tumor
• Humans
• Mice, Inbred C57BL
• Microtubules (metabolism)
• Mouth Neoplasms (metabolism)
• Squamous Cell Carcinoma of Head and Neck (metabolism)
• Wnt Signaling Pathway (physiology)
• beta Catenin (metabolism)
• Mice