title: Autophagy sustains the survival of human pancreatic cancer PANC-1 cells under extreme nutrient deprivation conditions.
abstract: Pancreatic ductal adenocarcinomas are an extremely aggressive and devastating type of cancer with high mortality. Given the dense stroma and poor vascularization, accessibility to nutrients is limited in the tumor microenvironment. Here, we aimed to elucidate the role of autophagy in promoting the survival of human pancreatic cancer PANC-1 cells exposed to nutrient-deprived media (NDM) lacking glucose, amino acids, and serum. NDM inhibited Akt activity and phosphorylation of p70 S6K, and induced AMPK activation and mitochondrial depolarization. NDM also time-dependently increased LC3-II accumulation, number of GFP-LC3 puncta, and colocalization between GFP-LC3 and lysosomes. These results suggested that autophagy was progressively activated through Akt- and AMPK-mTOR pathway in nutrient-deficient PANC-1 cells. Autophagy inhibitors (chloroquine and wortmannin) or silencing of Atg5 augmented PANC-1 cell death in NDM. In cells exposed to NDM, chloroquine and wortmannin induced apoptosis and Z-VAD-fmk inhibited cytotoxicity of these inhibitors. These data demonstrate that autophagy is anti-apoptotic and sustains the survival of PANC-1 cells following extreme nutrient deprivation. Autophagy modulation may be a viable therapeutic option for cancer cells located in the core of solid tumors with a nutrient-deficient microenvironment.
authors.affiliation: College of Pharmacy, Ajou University, Suwon, Gyeonggido 443-749, Republic of Korea.
authors.forename: Sang Eun
authors.initials: SE
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Ajou University, Suwon, Gyeonggido 443-749, Republic of Korea.
authors.forename: Hye-Jin
authors.initials: HJ
authors.lastname: Park
authors.affiliation: College of Pharmacy, Ajou University, Suwon, Gyeonggido 443-749, Republic of Korea.
authors.forename: Hye Kyoung
authors.initials: HK
authors.lastname: Jeong
authors.affiliation: College of Pharmacy, Ajou University, Suwon, Gyeonggido 443-749, Republic of Korea.
authors.forename: Mi-Jung
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Ajou University, Suwon, Gyeonggido 443-749, Republic of Korea.
authors.forename: Minyeong
authors.initials: M
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Hanyang University, Ansan, Gyeonggido 426-791, Republic of Korea.
authors.forename: Ok-Nam
authors.initials: ON
authors.lastname: Bae
authors.affiliation: College of Pharmacy, Ajou University, Suwon, Gyeonggido 443-749, Republic of Korea. Electronic address: shbaek@ajou.ac.kr.
authors.forename: Seung-Hoon
authors.initials: SH
authors.lastname: Baek
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000596:Amino Acids / Q000378:metabolism; D000730:Androstadienes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D006801:Humans; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000077191:Wortmannin
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D000596:Amino Acids; D000730:Androstadienes; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D002738:Chloroquine; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose; D000077191:Wortmannin
keywords: Apoptosis; Autophagy; Extreme nutrient deprivation; PANC-1; Survival