Stress-induced cleavage of Myc promotes cancer cell survival

Maralice Conacci-Sorrell, Celine Ngouenet, Sarah Anderson, Thomas Brabletz, Robert N. Eisenman

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

Evasion of apoptosis is critical in Myc-induced tumor progression. Here we report that cancer cells evade death under stress by activating calpain-mediated proteolysis of Myc. This generates Myc-nick, a cytoplasmic, transcriptionally inactive cleavage product of Myc. We found conversion of Myc into Myc-nick in cell lines and tissues derived from multiple cancers. In colon cancer, the production of Myc-nick is enhanced under stress conditions such as hypoxia and nutrient deprivation. Under these conditions, ectopic expression of Myc-nick promotes anchorage-independent growth and cell survival at least in part by promoting autophagy. Myc-nick also delays colon cancer cell death after treatment with chemotherapeutic drugs such as etoposide, cisplatin, and imatinib. Furthermore, colon cancer cells expressing a cleavage-resistant form of Myc undergo extensive apoptosis but are rescued by overexpression of Myc-nick. We also found that ectopic expression of Myc-nick results in the induction of the actin-bundling protein fascin, formation of filopodia, and increased cell motility-all mediators of tumor metastasis. Myc-nick-induced survival, autophagy, and motility require Myc box II (MBII), a region of Myc-nick that recruits acetyltransferases that in turn modify cytoplasmic proteins, including a-tubulin and ATG3. Our results suggest that Myc-nick-induced survival and motility contribute to colon cancer progression and metastasis.

Original languageEnglish (US)
Pages (from-to)689-707
Number of pages19
JournalGenes and Development
Volume28
Issue number7
DOIs
StatePublished - Apr 1 2014

Keywords

  • Autophagy
  • Fascin
  • Hypoxia
  • Motility
  • Myc
  • Myc-nick

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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