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Colorectal cancer-related mutant KRAS alleles function as positive regulators of autophagy

2015; Impact Journals LLC; Volume: 6; Issue: 31 Linguagem: Inglês

10.18632/oncotarget.5021

1949-2553

Sara Alves, Lisandra Castro, Maria Sofia Fernandes, Rita Francisco, Paula Alexandra Martins Cosme Vieira de Castro, Muriel Priault, Susana R. Chaves, Mary Pat Moyer, Carla Oliveíra, Raquel Seruca, Manuela Côrte‐Real, Maria João Sousa, Ana Preto,

Calcium signaling and nucleotide metabolism

// Sara Alves 1 , Lisandra Castro 1 , Maria Sofia Fernandes 3 , Rita Francisco 1 , Paula Castro 1 , Muriel Priault 2 , Susana Rodrigues Chaves 1 , Mary Pat Moyer 4 , Carla Oliveira 3 , Raquel Seruca 3 , Manuela Côrte-Real 1 , Maria João Sousa 1, * , Ana Preto 1, * 1 CBMA - Centre of Molecular and Environmental Biology, Department of Biology, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal 2 CNRS, UMR5095, University de Bordeaux 2, Bordeaux, France 3 IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal 4 INCELL Corporation, San Antonio, Texas, USA * These authors have contributed equally to this work Correspondence to: Ana Preto, e-mail: apreto@bio.uminho.pt Keywords: autophagy, KRAS mutations, colorectal cancer, humanized yeast, non-cancer colon cells Received: March 27, 2015 Accepted: September 14, 2015 Published: September 25, 2015 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 .