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

39 Citations (Scopus)

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

Fingerprint

Colonic Neoplasms
Cell Survival
Autophagy
Neoplasms
Cell Death
Apoptosis
Neoplasm Metastasis
Acetyltransferases
Pseudopodia
Calpain
Etoposide
Tubulin
Cisplatin
Proteolysis
Cell Movement
Actins
Proteins
Cell Line
Food
Growth

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Stress-induced cleavage of Myc promotes cancer cell survival. / Conacci-Sorrell, Maralice; Ngouenet, Celine; Anderson, Sarah; Brabletz, Thomas; Eisenman, Robert N.

In: Genes and Development, Vol. 28, No. 7, 01.04.2014, p. 689-707.

Research output: Contribution to journalArticle

Conacci-Sorrell, M, Ngouenet, C, Anderson, S, Brabletz, T & Eisenman, RN 2014, 'Stress-induced cleavage of Myc promotes cancer cell survival', Genes and Development, vol. 28, no. 7, pp. 689-707. https://doi.org/10.1101/gad.231894.113
Conacci-Sorrell, Maralice ; Ngouenet, Celine ; Anderson, Sarah ; Brabletz, Thomas ; Eisenman, Robert N. / Stress-induced cleavage of Myc promotes cancer cell survival. In: Genes and Development. 2014 ; Vol. 28, No. 7. pp. 689-707.
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