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, Ana Preto

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)30787-30802
Number of pages16
JournalOncotarget
Volume6
Issue number31
DOIs
StatePublished - 2015
Externally publishedYes

Keywords

  • Autophagy
  • Colorectal cancer
  • Humanized yeast
  • KRAS mutations
  • Non-cancer colon cells

ASJC Scopus subject areas

  • Oncology

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