title: Catabolic pathways regulated by mTORC1 are pivotal for survival and growth of cancer cells expressing mutant Ras.
abstract: Oncogenic Ras stimulates macropinocytosis, a clathrin-independent endocytosis that increases the uptake of extracellular fluid. However, the functional significance of and regulatory mechanisms driving macropinocytosis in cancer cells remain largely unknown. Here, we show that extracellular macromolecules, such as albumin, internalized by Ras-expressing cells can support growth and survival under the nutrient-deprived conditions like those found in tumors. Moreover, we demonstrate that autophagy, a lysosome-mediated catabolic pathway, is required for the uptake and degradation of macropinocytic vesicles. Intracellular metabolites derived from macropinocytosis and autophagy directly influence the activity and localization of mTOR, which is ultimately responsible for the restoration of cell growth. Surprisingly, suppression of mTORC1, which typically triggers anabolic processes, facilitates macropinocytosis and thus supports cell growth and survival under the nutrient-deprived conditions. In a mouse xenograft model of pancreatic ductal adenocarcinoma, concomitant inhibition of macropinocytosis/autophagy and mTOR activity resulted in antitumor effects. These data suggest that novel anti-cancer strategies interrupting these metabolic processes and related signaling molecules may represent promising therapeutic avenues.
authors.affiliation: Comparative Biomedicine Research Branch, Division of Cancer Biology, National Cancer Center, Ilsandong-gu, Goyang-si, Gyeonggi-do, Republic of Korea.
authors.forename: Suhyun
authors.initials: S
authors.lastname: Sung
authors.affiliation: Comparative Biomedicine Research Branch, Division of Cancer Biology, National Cancer Center, Ilsandong-gu, Goyang-si, Gyeonggi-do, Republic of Korea.
authors.forename: Jungwon
authors.initials: J
authors.lastname: Choi
authors.affiliation: Comparative Biomedicine Research Branch, Division of Cancer Biology, National Cancer Center, Ilsandong-gu, Goyang-si, Gyeonggi-do, Republic of Korea.
authors.forename: Heesun
authors.initials: H
authors.lastname: Cheong
mesh_terms: D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D015153:Blotting, Western; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D046912:Multiprotein Complexes / Q000378:metabolism*; D009154:Mutation / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D010873:Pinocytosis / Q000502:physiology*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics*
chemical_list: D046912:Multiprotein Complexes; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D018631:ras Proteins
keywords: KRas; autophagy; mTORC1; macropinocytosis; pancreatic ductal adenocarcinoma (PDA)