title: Autophagy is required for PDAC glutamine metabolism.
abstract: Macroautophagy (autophagy) is believed to maintain energy homeostasis by degrading unnecessary cellular components and molecules. Its implication in regulating cancer metabolism recently started to be uncovered. However, the precise roles of autophagy in cancer metabolism are still unclear. Here, we show that autophagy plays a critical role in glutamine metabolism, which is required for tumor survival. Pancreatic ductal adenocarcinoma (PDAC) cells require both autophagy and typical glutamine transporters to maintain intracellular glutamine levels. Glutamine deprivation, but not that of glucose, led to the activation of macropinocytosis-associated autophagy through TFEB induction and translocation into the nucleus. In contrast, glutamine uptake increased as a compensatory response to decreased intracellular glutamine levels upon autophagy inhibition. Moreover, autophagy inhibition and glutamine deprivation did not induce cell death, while glutamine deprivation dramatically activated apoptotic cell death upon autophagy inhibition. Interestingly, the addition of α-ketoglutarate significantly rescued the apoptotic cell death caused by the combination of the inhibition of autophagy with glutamine deprivation. Our data suggest that macropinocytosis-associated autophagy is a critical process providing glutamine for anaplerosis of the TCA cycle in PDAC. Thus, targeting both autophagy and glutamine metabolism to completely block glutamine supply may provide new therapeutic approaches to treat refractory tumors.
authors.affiliation: Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
authors.forename: Ju-Won
authors.initials: JW
authors.lastname: Seo
authors.affiliation: Comparative Biomedicine Research Branch, Division of Cancer Biology, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi-do 410-769, Republic of Korea.
authors.forename: Jungwon
authors.initials: J
authors.lastname: Choi
authors.affiliation: Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
authors.forename: So-Yeon
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Comparative Biomedicine Research Branch, Division of Cancer Biology, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi-do 410-769, Republic of Korea.
authors.forename: Suhyun
authors.initials: S
authors.lastname: Sung
authors.affiliation: Biomedical research center, Department of Convergence medicine, Asan Institute for Life Sciences, Asan Medical Center.
authors.forename: Hyun Ju
authors.initials: HJ
authors.lastname: Yoo
authors.affiliation: Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
authors.forename: Min-Ji
authors.initials: MJ
authors.lastname: Kang
authors.affiliation: Comparative Biomedicine Research Branch, Division of Cancer Biology, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi-do 410-769, Republic of Korea.|Graduate School of Cancer Science &Policy, National Cancer Center, Goyang 410-769, Republic of Korea.
authors.forename: Heesun
authors.initials: H
authors.lastname: Cheong
authors.affiliation: Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.|Asan Institute for Life Sciences, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea.
authors.forename: Jaekyoung
authors.initials: J
authors.lastname: Son
mesh_terms: D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D001692:Biological Transport; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival; D002952:Citric Acid Cycle; D005260:Female; D005947:Glucose / Q000172:deficiency; D005973:Glutamine / Q000172:deficiency / Q000378:metabolism*; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism; D010873:Pinocytosis; D018631:ras Proteins / Q000378:metabolism
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D050505:Mutant Proteins; C064972:TFEB protein, human; D005973:Glutamine; D018631:ras Proteins; D005947:Glucose