Astrocyte elevated gene-1 induces protective autophagy.
Astrocyte-elevated gene-1 (AEG-1) expression increases in multiple cancers and plays a crucial role in oncogenic transformation and angiogenesis, which are essential components in tumor cell development, growth, and progression to metastasis. Moreover, AEG-1 directly contributes to resistance to chemotherapeutic drugs, another important hallmark of aggressive cancers. In the present study, we document that AEG-1 mediates protective autophagy, an important regulator of cancer survival under metabolic stress and resistance to apoptosis, which may underlie its significant cancer-promoting properties. AEG-1 induces noncanonical autophagy involving an increase in expression of ATG5. AEG-1 decreases the ATP/AMP ratio, resulting in diminished cellular metabolism and activation of AMP kinase, which induces AMPK/mammalian target of rapamycin-dependent autophagy. Inhibition of AMPK by siAMPK or compound C decreases expression of ATG5, ultimately attenuating AEG-1-induced autophagy. AEG-1 protects normal cells from serum starvation-induced death through protective autophagy, and inhibition of AEG-1-induced autophagy results in serum starvation-induced cell death. We also show that AEG-1-mediated chemoresistance is because of protective autophagy and inhibition of AEG-1 results in a decrease in protective autophagy and chemosensitization of cancer cells. In summary, the present study reveals a previously unknown aspect of AEG-1 function by identifying it as a potential regulator of protective autophagy, an important feature of AEG-1 that may contribute to its tumor-promoting properties.
Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.
Sujit K
SK
Bhutia
Timothy P
TP
Kegelman
Swadesh K
SK
Das
Belal
B
Azab
Zhao-Zhong
ZZ
Su
Seok-Geun
SG
Lee
Devanand
D
Sarkar
Paul B
PB
Fisher
D000249:Adenosine Monophosphate / Q000235:genetics / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000235:genetics / Q000378:metabolism; D000263:Adenylate Kinase; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002461:Cell Line, Transformed; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D016601:RNA-Binding Proteins; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
C502778:ATG5 protein, human; D000071187:Autophagy-Related Protein 5; D015815:Cell Adhesion Molecules; C483039:MTDH protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D011720:Pyrazoles; D011743:Pyrimidines; D016601:RNA-Binding Proteins; C516138:dorsomorphin; D000249:Adenosine Monophosphate; D000255:Adenosine Triphosphate; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D000263:Adenylate Kinase