Oxidized low-density lipoproteins upregulate proline oxidase to initiate ROS-dependent autophagy.
Epidemiological studies showed that high levels of oxidized low-density lipoproteins (oxLDLs) are associated with increased cancer risk. We examined the direct effect of physiologic concentrations oxLDL on cancer cells. OxLDLs were cytotoxic and activate both apoptosis and autophagy. OxLDLs have ligands for peroxisome proliferator-activated receptor gamma and upregulated proline oxidase (POX) through this nuclear receptor. We identified 7-ketocholesterol (7KC) as a main component responsible for the latter. To elucidate the role of POX in oxLDL-mediated cytotoxicity, we knocked down POX via small interfering RNA and found that this (i) further reduced viability of cancer cells treated with oxLDL; (ii) decreased oxLDL-associated reactive oxygen species generation; (iii) decreased autophagy measured via beclin-1 protein level and light-chain 3 protein (LC3)-I into LC3-II conversion. Using POX-expressing cell model, we established that single POX overexpression was sufficient to activate autophagy. Thus, it led to autophagosomes accumulation and increased conversion of LC3-I into LC3-II. Moreover, beclin-1 gene expression was directly dependent on POX catalytic activity, namely the generation of POX-dependent superoxide. We conclude that POX is critical in the cellular response to the noxious effects of oxLDL by activating protective autophagy.
Zabirnyk
Olga
O
Metabolism and Cancer Susceptibility Section, Laboratory of Comparative Carcinogenesis, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702-1201, USA.
Liu
Wei
W
Khalil
Shadi
S
Sharma
Anit
A
Phang
James M
JM
D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006801:Humans; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008297:Male; D008315:Malondialdehyde / Q000032:analysis; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D047495:PPAR gamma / Q000502:physiology; D011394:Proline Oxidase / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000502:physiology; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis; D015854:Up-Regulation / Q000187:drug effects
D008077:Lipoproteins, LDL; D009363:Neoplasm Proteins; D047495:PPAR gamma; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins; D017392:Thiobarbituric Acid Reactive Substances; C099252:oxidized low density lipoprotein; D008315:Malondialdehyde; D011394:Proline Oxidase