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Stress Signaling In Development And Carcinogenesis : Role Of AMP-Activated Protein Kinase

Electronic Theses of Indian Institute of Science

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Title Stress Signaling In Development And Carcinogenesis : Role Of AMP-Activated Protein Kinase
 
Creator Kumar, Hindupur Sravanth
 
Subject Carcinoma Protein
Protein Kinase
AMP-Activated Protein Kinase
Autophagy
Metastasis
Epithelial-Mesenchymal Transition
Carcinogenesis
AMPK Signaling
AMPK Phosphorylates
Human Mammary Epithelial Cells
Molecular Biology
 
Description Rapidly growing tumor cells outgrow their blood supply resulting in a microenvironment with reduced oxygen and nutrients. Using an in vitro transformation model we found that cancer cells expressing the SV40 ST antigen (+ST cells) are more resistant to glucose deprivation-induced cell death than cells lacking the SV40 ST antigen (−ST cells). Mechanistically, we found that the ST antigen mediates this effect by activating a nutrient-sensing kinase, AMP-activated protein kinase (AMPK). We further show that AMPK mediates its effects, at least in part, by inhibiting mTOR (mammalian target of rapamycin), thereby shutting down protein translation, and by inducing autophagy as an alternate energy source.
Resistance to anoikis upon anchorage-deprivation is yet another form of stress tolerated by both normal stem/progenitor cells of various tissues in our body and by cancer cells. Using mammospheres as a model to enrich for stem/progenitor cells we found that mammosphere formation is accompanied with increased activation of AMPK. Concomitant with AMPK activation, we detected increased phosphorylation of the anti-apoptotic protein PED/PEA15. We further demonstrate that AMPK directly interacts with and phosphorylates PEA15 at Ser116, thus establishing PEA15 as a new AMPK target. Thus, our study has identified AMPK-PEA15 signaling as a key component of sphere formation by both normal and cancerous breast tissues.
During metastasis, epithelial cells lose attachments to their neighbors, acquire a mesenchymal-like morphology, a process termed as epithelial-mesenchymal transition (EMT) and become motile. Our results indicate that AMPK regulates EMT by both transcriptional and post-translational modification of EMT-inducing transcription factor, Twist.
Thus, our study has identified a role for AMPK in nutrient deprivation, anchorage-independent growth, and epithelial-mesenchymal transition involved in metastasis. In addition, we have identified two novel substrates of AMPK, PEA15 and Twist, that may play key roles in cancer progression. Thus, our study suggests that targeting AMPK, or its newly identified substrates, can be explored as possible anti-cancer mechanisms.
 
Contributor Rangarajan, Annapoorni
 
Date 2013-08-05T07:40:19Z
2013-08-05T07:40:19Z
2013-08-05
2011-10
 
Type Thesis
 
Identifier http://etd.iisc.ernet.in/handle/2005/2189
http://etd.ncsi.iisc.ernet.in/abstracts/2797/G25118-Abs.pdf
 
Language en_US
 
Relation G25118