title: Endoplasmic reticulum stress induced by 2-deoxyglucose but not glucose starvation activates AMPK through CaMKKβ leading to autophagy.
abstract: Autophagy, a well-conserved cellular self-eating process, has been shown to play a critical role in the pathophysiology of cancer. Previously, we reported that under normal O₂ conditions (21% O₂), the dual glucose metabolism inhibitor 2-deoxyglucose (2-DG) activates a cytoprotective autophagic response in cancer cells mainly through the induction of endoplasmic reticulum (ER) stress rather than ATP² reduction. However, the pathway(s) by which this occurs was unknown. Here, we find that ER stress induced by 2-DG as well as tunicamycin activates AMPK via Ca²⁺-CaMKKβ leading to stimulation of autophagy. These results suggest a new role for AMPK as a sensor of ER stress. In contrast, we find that although physiologic glucose starvation (GS) leads to ER stress which contributes to autophagy activation, it does so by a different mechanism. In addition to ER stress, GS also stimulates autophagy through lowering ATP and activating the canonical LKB1-AMPK energy sensing pathway as well as through increasing reactive oxygen species resulting in the activation of ERK. Furthermore, under hypoxia we observe that both 2-DG and GS inhibit rather than activate autophagy. This inhibition correlates with dramatically depleted ATP levels, and occurs through reduction of the PI3K III-Beclin1 complex for autophagy initiation, blockage of the conjugation of ATG12 to ATG5 for autophagosome expansion, as well as inhibition of the functional lysosomal compartment for autophagic degradation. Taken together, our data support a model where under normoxia therapeutic (2-DG) and physiologic (GS) glucose restriction differentially activate autophagy, while under hypoxia they similarly inhibit it.
authors.affiliation: Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, 1550 NW 10th Avenue, Fox Building #406, Miami, FL 33136, USA.
authors.forename: Haibin
authors.initials: H
authors.lastname: Xi
authors.forename: Julio C
authors.initials: JC
authors.lastname: Barredo
authors.forename: Jaime R
authors.initials: JR
authors.lastname: Merchan
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Lampidis
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000255:Adenosine Triphosphate / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000235:genetics* / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D003847:Deoxyglucose / Q000172:deficiency* / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000172:deficiency* / Q000494:pharmacology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species; D015398:Signal Transduction / Q000187:drug effects; D014415:Tunicamycin / Q000494:pharmacology
chemical_list: D000091162:AMP-Activated Protein Kinase Kinases; D000255:Adenosine Triphosphate; D051017:Apoptosis Regulatory Proteins; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D003847:Deoxyglucose; D048049:Extracellular Signal-Regulated MAP Kinases; D005947:Glucose; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D017382:Reactive Oxygen Species; D014415:Tunicamycin; C502778:ATG5 protein, human; C491997:BECN1 protein, human; C109790:STK11 protein, human