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Inhibition of breast cancer invasion by TIS21/BTG2/Pc3-Akt1-Sp1-Nox4 pathway targeting actin nucleators, mDia genes

Oncogene volume 35, pages 83–93 (2016)Cite this article

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Abstract

The mammalian homolog of Drosophila diaphanous (mDia), actin nucleator, has been known to participate in the process of invasion and metastasis of cancer cells via regulating a number of actin-related biological processes. We have previously reported that tumor suppressor TIS21/BTG2/Pc3 (TIS21) inhibits invadopodia formation by downregulating reactive oxygen species (ROS) in MDA-MB-231 cells. We herein report that TIS21/BTG2/Pc3 downregulates diaphanous-related formin (DRF) expression via reducing NADPH oxidase 4 (Nox4)-derived ROS generation by Akt1 activation and subsequently impairs invasion activity of the highly invasive breast cancer cells. Knockdown of Akt1 by RNA interference recovered the TIS21/BTG2/Pc3-inhibited F-actin remodeling and ROS generation by recovering Nox4 expression. Furthermore, Sp1-mediated Nox4 transcription was downregulated by TIS21/BTG2/Pc3-Akt1 signals, leading to the inhibition of cancer cell invasion via F-actin remodeling by mDia genes. To our best knowledge, this is the first study to show that TIS21/BTG2/Pc3-Akt1 inhibited Sp1-Nox4-ROS cascade, subsequently reducing invasion activity via inhibition of mDia family genes.

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Acknowledgements

Authors greatly appreciate Professor Young-Joon Chwae for his kind help in lucigenin-enhanced chemiluminescence assay, excellent advice for statistical analysis by Professor Seung-Soo Sheen, technical help for two-photon fluorescence microscopy by Cheol Ho Heo and careful reading of this manuscript by Professor Woon Ki Paik at Ajou University School of Medicine. This work was supported by a grant of the Korea Health technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A121725) and a grant from the National R&D Program for Cancer Control, Ministry for Health and Welfare, Republic of Korea (131280).

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  1. Departments of Biochemistry and Molecular Biology, Ajou University School of Medicine, and Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon, Korea,

    J-A Choi & I K Lim

  2. Department of Surgery, Ajou University School of Medicine, Suwon, Korea,

    Y S Jung & J Y Kim

  3. Department of Energy Systems Research, Ajou University, Suwon, Korea,

    H M Kim

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Choi, JA., Jung, Y., Kim, J. et al. Inhibition of breast cancer invasion by TIS21/BTG2/Pc3-Akt1-Sp1-Nox4 pathway targeting actin nucleators, mDia genes. Oncogene 35, 83–93 (2016). https://doi.org/10.1038/onc.2015.64

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