2,3,5,6-Tetramethylpyrazine Targets Epithelial-Mesenchymal Transition by Abrogating Manganese Superoxide Dismutase Expression and TGFβ-Driven Signaling Cascades in Colon Cancer Cells
Young Yun Jung,
Chakrabhavi Dhananjaya Mohan,
Huiyan Eng,
Acharan S. Narula,
Ojas A. Namjoshi,
Bruce E. Blough,
Kanchugarakoppal S. Rangappa,
Gautam Sethi,
Alan Prem Kumar,
Kwang Seok Ahn
Affiliations
Young Yun Jung
Department of Science in Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea
Chakrabhavi Dhananjaya Mohan
Department of Studies in Molecular Biology, University of Mysore, Manasagangotri, Mysore 570006, India
Huiyan Eng
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
Acharan S. Narula
Narula Research, Chapel Hill, NC 27516, USA
Ojas A. Namjoshi
Engine Biosciences, 733 Industrial Rd., San Carlos, CA 94070, USA
Bruce E. Blough
Center for Drug Discovery, RTI International, Research Triangle Park, Durham, NC 27616, USA
Kanchugarakoppal S. Rangappa
Institution of Excellence, Vijnana Bhavan, University of Mysore, Manasagangotri, Mysore 570006, India
Gautam Sethi
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
Alan Prem Kumar
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
Kwang Seok Ahn
Department of Science in Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea
Epithelial-mesenchymal transition (EMT) is a crucial process in which the polarized epithelial cells acquire the properties of mesenchymal cells and gain invasive properties. We have previously demonstrated that manganese superoxide dismutase (MnSOD) can regulate the EMT phenotype by modulating the intracellular reactive oxygen species. In this report, we have demonstrated the EMT-suppressive effects of 2,3,5,6-Tetramethylpyrazine (TMP, an alkaloid isolated from Chuanxiong) in colon cancer cells. TMP suppressed the expression of MnSOD, fibronectin, vimentin, MMP-9, and N-cadherin with a parallel elevation of occludin and E-cadherin in unstimulated and TGFβ-stimulated cells. Functionally, TMP treatment reduced the proliferation, migration, and invasion of colon cancer cells. TMP treatment also modulated constitutive activated as well as TGFβ-stimulated PI3K/Akt/mTOR, Wnt/GSK3/β-catenin, and MAPK signaling pathways. TMP also inhibited the EMT program in the colon cancer cells-transfected with pcDNA3-MnSOD through modulation of MnSOD, EMT-related proteins, and oncogenic pathways. Overall, these data indicated that TMP may inhibit the EMT program through MnSOD-mediated abrogation of multiple signaling events in colon cancer cells.
