title: Colorectal cancer-related mutant KRAS alleles function as positive regulators of autophagy.
abstract: The recent interest to modulate autophagy in cancer therapy has been hampered by the dual roles of this conserved catabolic process in cancer, highlighting the need for tailored approaches. Since RAS isoforms have been implicated in autophagy regulation and mutation of the KRAS oncogene is highly frequent in colorectal cancer (CRC), we questioned whether/how mutant KRAS alleles regulate autophagy in CRC and its implications. We established two original models, KRAS-humanized yeast and KRAS-non-cancer colon cells and showed that expression of mutated KRAS up-regulates starvation-induced autophagy in both. Accordingly, KRAS down-regulation inhibited autophagy in CRC-derived cells harboring KRAS mutations. We further show that KRAS-induced autophagy proceeds via up-regulation of the MEK/ERK pathway in both colon models and that KRAS and autophagy contribute to CRC cell survival during starvation. Since KRAS inhibitors have proven difficult to develop, our results suggest using autophagy inhibitors as a combined/alternative therapeutic approach in CRCs with mutant KRAS.
authors.affiliation: CBMA - Centre of Molecular and Environmental Biology, Department of Biology, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal.
authors.forename: Sara
authors.initials: S
authors.lastname: Alves
authors.affiliation: CBMA - Centre of Molecular and Environmental Biology, Department of Biology, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal.
authors.forename: Lisandra
authors.initials: L
authors.lastname: Castro
authors.affiliation: IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
authors.forename: Maria Sofia
authors.initials: MS
authors.lastname: Fernandes
authors.affiliation: CBMA - Centre of Molecular and Environmental Biology, Department of Biology, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal.
authors.forename: Rita
authors.initials: R
authors.lastname: Francisco
authors.affiliation: CBMA - Centre of Molecular and Environmental Biology, Department of Biology, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal.
authors.forename: Paula
authors.initials: P
authors.lastname: Castro
authors.affiliation: CNRS, UMR5095, University de Bordeaux 2, Bordeaux, France.
authors.forename: Muriel
authors.initials: M
authors.lastname: Priault
authors.affiliation: CBMA - Centre of Molecular and Environmental Biology, Department of Biology, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal.
authors.forename: Susana Rodrigues
authors.initials: SR
authors.lastname: Chaves
authors.affiliation: INCELL Corporation, San Antonio, Texas, USA.
authors.forename: Mary Pat
authors.initials: MP
authors.lastname: Moyer
authors.affiliation: IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
authors.forename: Carla
authors.initials: C
authors.lastname: Oliveira
authors.affiliation: IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
authors.forename: Raquel
authors.initials: R
authors.lastname: Seruca
authors.affiliation: CBMA - Centre of Molecular and Environmental Biology, Department of Biology, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal.
authors.forename: Manuela
authors.initials: M
authors.lastname: Côrte-Real
authors.affiliation: CBMA - Centre of Molecular and Environmental Biology, Department of Biology, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal.
authors.forename: Maria João
authors.initials: MJ
authors.lastname: Sousa
authors.affiliation: CBMA - Centre of Molecular and Environmental Biology, Department of Biology, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Preto
mesh_terms: D000483:Alleles; D001343:Autophagy / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D002470:Cell Survival; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005838:Genotype; D045325:HCT116 Cells; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009154:Mutation; D010641:Phenotype; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection
chemical_list: D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D016283:Proto-Oncogene Proteins p21(ras)
keywords: KRAS mutations; autophagy; colorectal cancer; humanized yeast; non-cancer colon cells