Oncotarget

Research Papers:

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

Sara Alves _, Lisandra Castro, Maria Sofia Fernandes, Rita Francisco, Paula Castro, Muriel Priault, Susana Rodrigues Chaves, Mary Pat Moyer, Carla Oliveira, Raquel Seruca, Manuela Côrte-Real, Maria João Sousa and Ana Preto

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Oncotarget. 2015; 6:30787-30802. https://doi.org/10.18632/oncotarget.5021

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Abstract

Sara Alves1, Lisandra Castro1, Maria Sofia Fernandes3, Rita Francisco1, Paula Castro1, Muriel Priault2, Susana Rodrigues Chaves1, Mary Pat Moyer4, Carla Oliveira3, Raquel Seruca3, Manuela Côrte-Real1, Maria João Sousa1,*, Ana Preto1,*

1CBMA - Centre of Molecular and Environmental Biology, Department of Biology, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal

2CNRS, UMR5095, University de Bordeaux 2, Bordeaux, France

3IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal

4INCELL 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.


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