Research Papers:

Metformin enhances TRAIL-induced apoptosis by Mcl-1 degradation via Mule in colorectal cancer cells

Seong Hye Park, Dae-Hee Lee, Jung Lim Kim, Bo Ram Kim, Yoo Jin Na, Min Jee Jo, Yoon A. Jeong, Suk-Young Lee, Sun Il Lee, Yong Yook Lee and Sang Cheul Oh _

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Oncotarget. 2016; 7:59503-59518. https://doi.org/10.18632/oncotarget.11147

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Seong Hye Park1,*, Dae-Hee Lee1,2,*, Jung Lim Kim2, Bo Ram Kim1, Yoo Jin Na1, Min Jee Jo1, Yoon A. Jeong2, Suk-Young Lee2, Sun Il Lee3, Yong Yook Lee4, Sang Cheul Oh1,2

1Brain Korea 21 Program for Biomedicine Science, Korea University College of Medicine, Korea University, Seoul, Republic of Korea

2Division of Oncology/Hematology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea

3Department of Surgery, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Republic of Korea

4The Korean Ginseng Research Institute, Daejeon, Republic of Korea

*These authors contributed equally to this work

Correspondence to:

Sang Cheul Oh, email: [email protected]

Keywords: metformin, TRAIL, CRC, Mcl-1, Noxa

Received: December 20, 2015     Accepted: July 06, 2016     Published: August 09, 2016


Metformin is an anti-diabetic drug with a promising anti-cancer potential. In this study, we show that subtoxic doses of metformin effectively sensitize human colorectal cancer (CRC) cells to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), which induces apoptosis. Metformin alone did not induce apoptosis, but significantly potentiated TRAIL-induced apoptosis in CRC cells. CRC cells treated with metformin and TRAIL showed activation of the intrinsic and extrinsic pathways of caspase activation. We attempted to elucidate the underlying mechanism, and found that metformin significantly reduced the protein levels of myeloid cell leukemia 1 (Mcl-1) in CRC cells and, the overexpression of Mcl-1 inhibited cell death induced by metformin and/or TRAIL. Further experiments revealed that metformin did not affect mRNA levels, but increased proteasomal degradation and protein stability of Mcl-1. Knockdown of Mule triggered a significant decrease of Mcl-1 polyubiquitination. Metformin caused the dissociation of Noxa from Mcl-1, which allowed the binding of the BH3-containing ubiquitin ligase Mule followed by Mcl-1ubiquitination and degradation. The metformin-induced degradation of Mcl-1 required E3 ligase Mule, which is responsible for the polyubiquitination of Mcl-1. Our study is the first report indicating that metformin enhances TRAIL-induced apoptosis through Noxa and favors the interaction between Mcl-1 and Mule, which consequently affects Mcl-1 ubiquitination.

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