High Glucose Induces Down-Regulated GRIM-19 Expression to Activate STAT3 Signaling and Promote Cell Proliferation in Cell Culture.
Recent studies indicated that Gene Associated with Retinoid-IFN-Induced Mortality 19 (GRIM-19), a newly discovered mitochondria-related protein, can regulate mitochondrial function and modulate cell viability possibly via interacting with STAT3 signal. In the present study we sought to test: 1) whether GRIM-19 is involved in high glucose (HG) induced altered cell metabolism in both cancer and cardiac cells, 2) whether GRIM-19/STAT3 signaling pathway plays a role in HG induced biological effects, especially whether AMPK activity could be involved. Our data showed that HG enhanced cell proliferation of both HeLa and H9C2 cells, which was closely associated with down-regulated GRIM-19 expression and increased phosphorylated STAT3 level. We showed that GRIM-19 knock-down alone in normal glucose cultured cells can also result in an increase in phosphorylated STAT3 level and enhanced proliferation capability, whereas GRIM-19 over-expression can abolished HG induced STAT3 activation and enhanced cell proliferation. Importantly, both down-regulated or over-expression of GRIM-19 increased lactate production in both HeLa and H9C2 cells. The activated STAT3 was responsible for increased cell proliferation as either AG-490, an inhibitor of JAK2, or siRNA targeting STAT3 can attenuate cell proliferation increased by HG. In addition, HG increased lactate acid levels in HeLa cells, which was also observed when GRIM-19 was genetically manipulated. However, HG did not affect the lactate levels in H9C2 cells. Of note, over-expression of GRIM-19 and silencing of STAT3 both increased lactate production in H9C2 cells. As expected, HG resulted in significant decreases in phosphorylated AMPKα levels in H9C2 cells, but not in HeLa cells. Interestingy, activation of AMPKα by metformin was associated with a reversal of the suppressed GRIM-19 expression in H9C2 cells, the fold of changes in GRIM-19 expression by metformin were much less in HeLa cells. Metformin did not affect the phosphorylated STAT3 lelvels, however, decreased its levels in H9C2, especially in the setting of HG culture. Not like HG alone which resulted in no changes in lactate acid in H9C2 cells, metformin can increase lactate acid levels in H9C2 cells. Increased lactate induced by metformin was also observed in HeLa cells.
State Key Discipline Division, Heart Center, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, People's Republic of China.
Yong-Guang
YG
Li
State Key Discipline Division, Heart Center, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, People's Republic of China.
Bei-Bei
BB
Han
State Key Discipline Division, Heart Center, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, People's Republic of China.
Feng
F
Li
Division of Cardiology, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang, People's Republic of China.
Jian-Wu
JW
Yu
State Key Discipline Division, Heart Center, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, People's Republic of China.
Zhi-Feng
ZF
Dong
State Key Discipline Division, Heart Center, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, People's Republic of China.
Geng-Ming
GM
Niu
State Key Discipline Division, Heart Center, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, People's Republic of China.
Yan-Wei
YW
Qing
State Key Discipline Division, Heart Center, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, People's Republic of China.
Jing-Bo
JB
Li
State Key Discipline Division, Heart Center, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, People's Republic of China.
Meng
M
Wei
State Key Discipline Division, Heart Center, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, People's Republic of China.|Provincial Key Laboratory of Cardiovascular Research, Department of Cardiology, Zhejiang University School of Medicine 2nd Affiliated Hospital, Hangzhou, Zhejiang, People's Republic of China.
Wei
W
Zhu
D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects*; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
D051017:Apoptosis Regulatory Proteins; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D009247:NADH, NADPH Oxidoreductases; C439057:NDUFA13 protein, human; D017868:Cyclic AMP-Dependent Protein Kinases; D005947:Glucose