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, Sang Cheul Oh

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)59503-59518
Number of pages16
JournalOncotarget
Volume7
Issue number37
DOIs
Publication statusPublished - 2016

Fingerprint

TNF-Related Apoptosis-Inducing Ligand
Myeloid Leukemia
Equidae
Metformin
Myeloid Cells
Colorectal Neoplasms
Apoptosis
Noxae
Ubiquitin-Protein Ligases
Protein Stability
Ubiquitination
Ligases
Caspases
Ubiquitin
Cell Death
Tumor Necrosis Factor-alpha

Keywords

  • CRC
  • Mcl-1
  • Metformin
  • Noxa
  • TRAIL

ASJC Scopus subject areas

  • Oncology

Cite this

Metformin enhances TRAIL-induced apoptosis by Mcl-1 degradation via Mule in colorectal cancer cells. / Park, Seong Hye; Lee, Dae Hee; Kim, Jung Lim; Kim, Bo Ram; Na, Yoo Jin; Jo, Min Jee; Jeong, Yoon A.; Lee, Suk Young; Lee, Sun Il; Lee, Yong Yook; Oh, Sang Cheul.

In: Oncotarget, Vol. 7, No. 37, 2016, p. 59503-59518.

Research output: Contribution to journalArticle

Park, SH, Lee, DH, Kim, JL, Kim, BR, Na, YJ, Jo, MJ, Jeong, YA, Lee, SY, Lee, SI, Lee, YY & Oh, SC 2016, 'Metformin enhances TRAIL-induced apoptosis by Mcl-1 degradation via Mule in colorectal cancer cells', Oncotarget, vol. 7, no. 37, pp. 59503-59518. https://doi.org/10.18632/oncotarget.11147
Park, Seong Hye ; Lee, Dae Hee ; Kim, Jung Lim ; Kim, Bo Ram ; Na, Yoo Jin ; Jo, Min Jee ; Jeong, Yoon A. ; Lee, Suk Young ; Lee, Sun Il ; Lee, Yong Yook ; Oh, Sang Cheul. / Metformin enhances TRAIL-induced apoptosis by Mcl-1 degradation via Mule in colorectal cancer cells. In: Oncotarget. 2016 ; Vol. 7, No. 37. pp. 59503-59518.
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