Cancer stem cells (CSCs) persist in tumors as a distinct population and may be causative in metastasis and relapse. CSC-rich tumors are associated with higher rates of metastasis and poor patient prognosis. Targeting CSCs therapeutically is challenging, since they seem to be resistant to standard chemotherapy. We have shown that a novel peptide agonist of bone morphogenetic protein (BMP) signaling, P123, is capable of inhibiting the growth of primary tumor cells by interacting with type I receptors selectively [activin receptor-like kinase 2 (ALK2) and ALK3, but not ALK6] and type II BMP receptors, activating SMAD 1/5/8 signaling and controlling the cell cycle pathway. Furthermore, the compound is capable of blocking transforming growth factor-β induced epithelial-to-mesenchymal transition (EMT) in primary tumor cells, a critical step for tumor progression and metastasis. In addition, we have investigated the effects of P123 on self-renewal, growth, differentiation (reversal of EMT) and apoptosis of isolated human breast CSCs. We have shown that P123 and BMP-7 reverse the EMT process in human breast CSCs, and inhibit self-renewal and growth. Moreover, compared with single treatment with paclitaxel, co-treatment with paclitaxel and P123 showed an increase in cell apoptosis. Together, these findings suggest that P123 has the therapeutic potential to suppress both bulk tumor cells and CSCs. We believe that P123 represents a new class of drugs that have the potential to eliminate the primary tumor, prevent reoccurrence and metastasis, and enhance the treatment of breast cancer.
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February 2017
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The surface of the catalytic subunit of protein phosphatase PP1 (central 3D-structure) has many binding sites for regulatory proteins that are embedded in regulatory networks (coloured circles linked by lines). Please see pp. 89–99 for more information. Image provided by Mathieu Bollen.
Review Article|
February 15 2017
Harnessing the BMP signaling pathway to control the formation of cancer stem cells by effects on epithelial-to-mesenchymal transition
Ashish Bosukonda;
Ashish Bosukonda
1Albany Medical College, Albany, NY, U.S.A.
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William D. Carlson
2Massachusetts General Hospital/Harvard Medical School, Boston, MA, U.S.A.
3Therapeutics by Design, Cambridge, MA, U.S.A.
Correspondence: William D. Carlson (wcarlson@partners.org; wcarlson@MGH.Harvard.edu)
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Publisher: Portland Press Ltd
Received:
October 01 2016
Revision Received:
December 05 2016
Accepted:
December 08 2016
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society
2017
Biochem Soc Trans (2017) 45 (1): 223–228.
Article history
Received:
October 01 2016
Revision Received:
December 05 2016
Accepted:
December 08 2016
Citation
Ashish Bosukonda, William D. Carlson; Harnessing the BMP signaling pathway to control the formation of cancer stem cells by effects on epithelial-to-mesenchymal transition. Biochem Soc Trans 8 February 2017; 45 (1): 223–228. doi: https://doi.org/10.1042/BST20160177
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