MUC1 oncoprotein promotes autophagy in a survival response to glucose deprivation.
Tumor cells survive under conditions of nutrient deprivation by mechanisms that are not fully understood. The MUC1 oncoprotein is aberrantly overexpressed by most human carcinomas and blocks oxidative stress-induced death. The present studies show that MUC1 inhibits the induction of necrosis in response to the deprivation of glucose. MUC1 suppressed glucose deprivation-induced increases in reactive oxygen species (ROS) and thereby depletion of ATP and cell death. Cells respond to oxidative stress and energy depletion with the induction of autophagy. Our results demonstrate that MUC1 blocks depletion of ATP and sustains growth of glucose-deprived cells by a mechanism sensitive to the autophagy inhibitor, 3-methyladenine. Silencing expression of ATG7, a protein essential for the formation of autophagic vacuoles, also attenuated the MUC1-sustained increases in ATP and growth in response to glucose deprivation. Moreover, we found that MUC1 stimulates AMPK activation and thereby promotes lysosomal turnover of LC3-II, a marker of starvation-induced autophagic activity. These results indicate that MUC1 suppresses glucose deprivation-induced increases in ROS and thereby promotes ATP production and survival. The findings also indicate that the overexpression of MUC1 as found in human cancers could provide a survival advantage in microenvironments with low glucose levels.
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Li
L
Yin
Surender
S
Kharbanda
Donald
D
Kufe
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D001343:Autophagy; D000071193:Autophagy-Related Protein 7; D015153:Blotting, Western; D002470:Cell Survival; D005947:Glucose / Q000378:metabolism*; D045325:HCT116 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D018396:Mucin-1 / Q000235:genetics / Q000378:metabolism*; D009336:Necrosis; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044764:Ubiquitin-Activating Enzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
C477012:MAP1LC3A protein, human; C060192:MUC1 protein, human; D008869:Microtubule-Associated Proteins; D018396:Mucin-1; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C025946:3-methyladenine; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D055372:AMP-Activated Protein Kinases; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7; D044764:Ubiquitin-Activating Enzymes; D005947:Glucose; D000225:Adenine