PMID- 30816444
OWN - NLM
STAT- MEDLINE
DCOM- 20190813
LR  - 20190813
IS  - 1791-2423 (Electronic)
IS  - 1019-6439 (Linking)
VI  - 54
IP  - 5
DP  - 2019 May
TI  - MUL1 E3 ligase regulates the antitumor effects of metformin in chemoresistant 
      ovarian cancer cells via AKT degradation.
PG  - 1833-1842
LID - 10.3892/ijo.2019.4730 [doi]
AB  - Chemoresistance is one of most critical clinical problems encountered when 
      treating patients with ovarian cancer, due to the fact that the disease is 
      usually diagnosed at advanced stages. Metformin is used as a first‑line drug for 
      the treatment of type 2 diabetes; however, drug repositioning studies have 
      revealed its antitumor effects, mainly mediated through AMP‑activated protein 
      kinase (AMPK) activation and AKT/mammalian target of rapamycin (mTOR) pathway 
      inhibition in various types of cancer, including drug‑resistant cancer cells. The 
      current study revealed that the novel antitumor mechanism of metformin is 
      mediated by regulation of mitochondrial E3 ubiquitin protein ligase 1 (MUL1) 
      expression that negatively regulates AKT. The results demonstrated that metformin 
      decreased the expression of AKT protein levels via MUL1 E3 ligase. In addition, 
      metformin increased both mRNA and protein levels of MUL1 and promoted degradation 
      of AKT in a proteasome‑dependent manner. Silencing MUL1 expression suppressed the 
      metformin‑mediated AKT degradation and its downstream effects. Cell cycle 
      analysis and a clonogenic assay demonstrated that knockdown of MUL1 significantly 
      diminished the antitumor effects of metformin. Together, these data indicate that 
      MUL1 regulates metformin‑mediated AKT degradation and the antitumor effects of 
      metformin in chemoresistant ovarian cancer cell lines.
FAU - Lee, Junwoo
AU  - Lee J
AD  - GeneCellPharm Corporation, Seoul 05836, Republic of Korea.
FAU - An, Sungkwan
AU  - An S
AD  - Research Institute for Molecular-Targeted Drugs, Department of Cosmetics 
      Engineering, Konkuk University, Seoul 05029, Republic of Korea.
FAU - Jung, Jin Hyuk
AU  - Jung JH
AD  - GeneCellPharm Corporation, Seoul 05836, Republic of Korea.
FAU - Kim, Karam
AU  - Kim K
AD  - GeneCellPharm Corporation, Seoul 05836, Republic of Korea.
FAU - Kim, Ji Yea
AU  - Kim JY
AD  - GeneCellPharm Corporation, Seoul 05836, Republic of Korea.
FAU - An, In-Sook
AU  - An IS
AD  - GeneCellPharm Corporation, Seoul 05836, Republic of Korea.
FAU - Bae, Seunghee
AU  - Bae S
AD  - Research Institute for Molecular-Targeted Drugs, Department of Cosmetics 
      Engineering, Konkuk University, Seoul 05029, Republic of Korea.
LA  - eng
PT  - Journal Article
DEP - 20190227
PL  - Greece
TA  - Int J Oncol
JT  - International journal of oncology
JID - 9306042
RN  - 9100L32L2N (Metformin)
RN  - EC 2.3.2.27 (MUL1 protein, human)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
MH  - Animals
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cell Survival/drug effects
MH  - Drug Repositioning
MH  - Drug Resistance, Neoplasm/*drug effects
MH  - Female
MH  - Humans
MH  - Metformin/*administration & dosage/pharmacology
MH  - Mice
MH  - Ovarian Neoplasms/*drug therapy/enzymology
MH  - Proteolysis
MH  - Proto-Oncogene Proteins c-akt/*metabolism
MH  - Ubiquitin-Protein Ligases/*metabolism
MH  - Xenograft Model Antitumor Assays
EDAT- 2019/03/01 06:00
MHDA- 2019/08/14 06:00
CRDT- 2019/03/01 06:00
PHST- 2018/07/19 00:00 [received]
PHST- 2019/01/30 00:00 [accepted]
PHST- 2019/03/01 06:00 [pubmed]
PHST- 2019/08/14 06:00 [medline]
PHST- 2019/03/01 06:00 [entrez]
AID - 10.3892/ijo.2019.4730 [doi]
PST - ppublish
SO  - Int J Oncol. 2019 May;54(5):1833-1842. doi: 10.3892/ijo.2019.4730. Epub 2019 Feb 
      27.