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The antitumor properties of metformin and phenformin reflect their ability to inhibit the actions of differentiated embryo chondrocyte 1

Authors Kuo CL, Hsieh Li SM, Liang SY, Liu ST, Huang LC, Wang WM, Yen LC, Huang SM

Received 1 April 2019

Accepted for publication 20 June 2019

Published 15 July 2019 Volume 2019:11 Pages 6567—6579

DOI https://doi.org/10.2147/CMAR.S210637

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Amy Norman

Peer reviewer comments 2

Editor who approved publication: Dr Antonella D'Anneo


Chun-Lin Kuo,1 Shu-Man Hsieh Li,*,2 Shu-Yi Liang,*,2 Shu-Ting Liu,2 Li-Chun Huang,2 Wei-Ming Wang,3 Li-Chen Yen,2,4 Shih-Ming Huang2

1Department of Orthopaedic Surgery, Tri-Service General Hospital, National Defense Medical Center, Taiwan, Republic of China; 2Department of Biochemistry, National Defense Medical Center, Taiwan, Republic of China; 3Department of Dermatology, Tri-Service General Hospital, National Defense Medical Center, Taiwan, Republic of China; 4Department of Microbiology and Immunology, National Defense Medical Center, Taiwan, Republic of China

*These authors contributed equally to this work

Background: Differentiated embryo chondrocyte 1 (DEC1) is a helix-loop-helix transcription factor that directly binds to the class B E-box in target genes. DEC1 exerts both pro-survival and pro-apoptotic effects in a cell- and tissue-dependent manner. Its actions play role the progression of cancer remains unclear.
Methods: We first examined the functional roles of DEC1 using the transient promoter reporter assay. Then, the knockdown of DEC1 expression was performed with the short hairpin RNA strategy in HeLa and A2058 cancer cell lines to check the cell cycle and mitochondrial function profile using the flow cytometry and Seahorse assays. We later clarified the role of DEC1 in the tumorigenesis using the colony formation, anchorage-independent growth assay, and cellular proliferation analysis.
Results: In the present study, we tested two guanide-containing drugs, metformin and phenformin, and found that both exhibit cytotoxicity against HeLa cervical carcinoma and A2058 melanoma cells. This effect was mediated, at least in part, through activation of the AMPK pathway; degradation of important cellular proteins, such as DEC1 and p53; and suppression of mitochondrial function, colony formation, and anchorage-independent cell proliferation. Our results further suggest that the cytotoxicity of metformin and phenformin reflect the impact of the repressive actions of DEC1 on gene expression, including DEC1 itself. This in turn suppresses both anchorage-independent growth and cell proliferation.
Conclusion: These findings provide several lines of evidence suggesting that DEC1 activity contributes to tumorigenicity and that the antitumor properties of biguanides reflect their ability to inhibit DEC1 functions.

Keywords: differentiated embryo chondrocyte 1, p53, metformin, phenformin, tumorigenesis

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