O-GlcNAc protein modification in cancer cells increases in response to glucose deprivation through glycogen degradation.
When cellular glucose concentrations fall below normal levels, in general the extent of protein O-GlcNAc modification (O-GlcNAcylation) decreases. However, recent reports demonstrated increased O-GlcNAcylation by glucose deprivation in HepG2 and Neuro-2a cells. Here, we report increased O-GlcNAcylation in non-small cell lung carcinoma A549 cells and various other cells in response to glucose deprivation. Although the level of O-GlcNAc transferase was unchanged, the enzyme contained less O-GlcNAc, and its activity was increased. Moreover, O-GlcNAcase activity was reduced. The studied cells contain glycogen, and we show that its degradation in response to glucose deprivation provides a source for UDP-GlcNAc required for increased O-GlcNAcylation under this condition. This required active glycogen phosphorylase and resulted in increased glutamine:fructose-6-phosphate amidotransferase, the first and rate-limiting enzyme in the hexosamine biosynthetic pathway. Interestingly, glucose deprivation reduced the amount of phosphofructokinase 1, a regulatory glycolytic enzyme, and blocked ATP synthesis. These findings suggest that glycogen is the source for increased O-GlcNAcylation but not for generating ATP in response to glucose deprivation and that this may be useful for cancer cells to survive.
Kang
Jeong Gu
JG
Department of Biology, Oral Cancer Research Institute, Korea.
Park
Sang Yoon
SY
Ji
Suena
S
Jang
Insook
I
Park
Sujin
S
Kim
Hyun Sil
HS
Kim
Sung-Min
SM
Yook
Jong In
JI
Park
Yong-Il
YI
Roth
Jürgen
J
Cho
Jin Won
JW
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000117:Acetylglucosamine / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D005947:Glucose / Q000378:metabolism*; D006003:Glycogen / Q000378:metabolism*; D006801:Humans; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism*; D011499:Protein Processing, Post-Translational
D006003:Glycogen; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase; D055372:AMP-Activated Protein Kinases; D005947:Glucose; D000117:Acetylglucosamine