Oncogenic RAS-induced downregulation of ATG12 is required for survival of malignant intestinal epithelial cells

Byong Hoon Yoo, Iman Aftab Khan, Ananda Koomson, Pramod Gowda, Takehiko Sasazuki, Senji Shirasawa, Shashi Gujar, Kirill V. Rosen

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

Activating mutations of RAS GTPase contribute to the progression of many cancers, including colorectal carcinoma. So far, attempts to develop treatments of mutant RAS-carrying cancers have been unsuccessful due to insufficient understanding of the salient mechanisms of RAS signaling. We found that RAS downregulates the protein ATG12 in colon cancer cells. ATG12 is a mediator of autophagy, a process of degradation and reutilization of cellular components. In addition, ATG12 can kill cells via autophagy-independent mechanisms. We established that RAS reduces ATG12 levels in cancer cells by accelerating its proteasomal degradation. We further observed that RAS-dependent ATG12 loss in these cells is mediated by protein kinases MAP2K/MEK and MAPK1/ERK2-MAPK3/ERK1, known effectors of RAS. We also demonstrated that the reversal of the effect of RAS on ATG12 achieved by the expression of exogenous ATG12 in cancer cells triggers both apoptotic and nonapoptotic signals and efficiently kills the cells. ATG12 is known to promote autophagy by forming covalent complexes with other autophagy mediators, such as ATG5. We found that the ability of ATG12 to kill oncogenic RAS-carrying malignant cells does not require covalent binding of ATG12 to other proteins. In summary, we have identified a novel mechanism by which oncogenic RAS promotes survival of malignant intestinal epithelial cells. This mechanism is driven by RAS-dependent loss of ATG12 in these cells.

Original languageEnglish
Pages (from-to)134-151
Number of pages18
JournalAutophagy
Volume14
Issue number1
DOIs
Publication statusPublished - Jan 2 2018

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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