Abstract
Metformin can suppress cell proliferation and viability by altering mitochondrial energy metabolism and by the activation of 5'-adenosine monophosphate-activated protein kinase (AMPK). The current study demonstrated that metformin-induced suppression of cell proliferation is further potentiated by AMPK-mediated suppression of β-catenin-dependent wingless-type (Wnt) signaling. Treatment with metformin reduced mitochondrial oxidative phosphorylation and glycolysis, leading to an energy imbalance that may induce AMPK phosphorylation in RKO cells. Metformin treatment also decreased β-catenin expression in the cytoplasm and nucleus. Active AMPK was revealed to be associated with β-catenin. The decrease in β-catenin expression was inhibited by proteosome inhibition through phosphorylation of β-catenin at serine 33/37. Given that nuclear translocation-associated phosphorylation of β-catenin at serine was maintained, the association of β-catenin with AMPK may sequester β-catenin in the cytoplasm and lead to proteosomal degradation. Furthermore, metformin-induced suppression of cell proliferation was partially recovered by AMPK inhibition, while metformin inhibited Wnt-mediated cell proliferation and β-catenin expression. The present results suggest that AMPK activation can suppress β-catenin-dependent Wnt signaling by cytoplasmic sequestering of β-catenin through AMPK, which further decreases cell proliferation in addition to metformin-induced mitochondrial dysfunction.
| Original language | English |
|---|---|
| Pages (from-to) | 2695-2702 |
| Number of pages | 8 |
| Journal | Oncology Letters |
| Volume | 17 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 2019 Mar 1 |
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Keywords
- 5'-adenosine monophosphate-activated protein kinase
- Adenosine 5'-triphosphate production
- Cell proliferation
- Metformin
- β-catenin
ASJC Scopus subject areas
- Oncology
- Cancer Research
Cite this
Metformin-activated AMPK regulates β-catenin to reduce cell proliferation in colon carcinoma RKO cells. / Park, Song Yi; Kim, Dasarang; Kee, Sun-Ho.
In: Oncology Letters, Vol. 17, No. 3, 01.03.2019, p. 2695-2702.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Metformin-activated AMPK regulates β-catenin to reduce cell proliferation in colon carcinoma RKO cells
AU - Park, Song Yi
AU - Kim, Dasarang
AU - Kee, Sun-Ho
PY - 2019/3/1
Y1 - 2019/3/1
N2 - Metformin can suppress cell proliferation and viability by altering mitochondrial energy metabolism and by the activation of 5'-adenosine monophosphate-activated protein kinase (AMPK). The current study demonstrated that metformin-induced suppression of cell proliferation is further potentiated by AMPK-mediated suppression of β-catenin-dependent wingless-type (Wnt) signaling. Treatment with metformin reduced mitochondrial oxidative phosphorylation and glycolysis, leading to an energy imbalance that may induce AMPK phosphorylation in RKO cells. Metformin treatment also decreased β-catenin expression in the cytoplasm and nucleus. Active AMPK was revealed to be associated with β-catenin. The decrease in β-catenin expression was inhibited by proteosome inhibition through phosphorylation of β-catenin at serine 33/37. Given that nuclear translocation-associated phosphorylation of β-catenin at serine was maintained, the association of β-catenin with AMPK may sequester β-catenin in the cytoplasm and lead to proteosomal degradation. Furthermore, metformin-induced suppression of cell proliferation was partially recovered by AMPK inhibition, while metformin inhibited Wnt-mediated cell proliferation and β-catenin expression. The present results suggest that AMPK activation can suppress β-catenin-dependent Wnt signaling by cytoplasmic sequestering of β-catenin through AMPK, which further decreases cell proliferation in addition to metformin-induced mitochondrial dysfunction.
AB - Metformin can suppress cell proliferation and viability by altering mitochondrial energy metabolism and by the activation of 5'-adenosine monophosphate-activated protein kinase (AMPK). The current study demonstrated that metformin-induced suppression of cell proliferation is further potentiated by AMPK-mediated suppression of β-catenin-dependent wingless-type (Wnt) signaling. Treatment with metformin reduced mitochondrial oxidative phosphorylation and glycolysis, leading to an energy imbalance that may induce AMPK phosphorylation in RKO cells. Metformin treatment also decreased β-catenin expression in the cytoplasm and nucleus. Active AMPK was revealed to be associated with β-catenin. The decrease in β-catenin expression was inhibited by proteosome inhibition through phosphorylation of β-catenin at serine 33/37. Given that nuclear translocation-associated phosphorylation of β-catenin at serine was maintained, the association of β-catenin with AMPK may sequester β-catenin in the cytoplasm and lead to proteosomal degradation. Furthermore, metformin-induced suppression of cell proliferation was partially recovered by AMPK inhibition, while metformin inhibited Wnt-mediated cell proliferation and β-catenin expression. The present results suggest that AMPK activation can suppress β-catenin-dependent Wnt signaling by cytoplasmic sequestering of β-catenin through AMPK, which further decreases cell proliferation in addition to metformin-induced mitochondrial dysfunction.
KW - 5'-adenosine monophosphate-activated protein kinase
KW - Adenosine 5'-triphosphate production
KW - Cell proliferation
KW - Metformin
KW - β-catenin
UR - http://www.scopus.com/inward/record.url?scp=85062149205&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85062149205&partnerID=8YFLogxK
U2 - 10.3892/ol.2019.9892
DO - 10.3892/ol.2019.9892
M3 - Article
AN - SCOPUS:85062149205
VL - 17
SP - 2695
EP - 2702
JO - Oncology Letters
JF - Oncology Letters
SN - 1792-1074
IS - 3
ER -