Anoikis, initiated by MCL-1 degradation and Bim induction, is deregulated during oncogenesis

Nicholas T. Woods, Hirohito Yamaguchi, Francis Y. Lee, Kapil N. Bhalla, Hong Gang Wang

Research output: Contribution to journalArticle

79 Scopus citations

Abstract

Anoikis, a Bax-dependent apoptosis triggered by detachment from the extracellular matrix, is often dysfunctional in metastatic cancer cells. Using wild-type and c-Src-transformed NIH3T3 cells as a model, we identified Mcl-1 degradation and Bim up-regulation as a critical determinant of anoikis initiation. Detachment rapidly degraded Mcl-1 via a GSK-3β-dependent proteasomal pathway and transcriptionally up-regulated Bim expression. Mcl-1 degradation in the presence of Bim was sufficient to induce anoikis. By analyzing nonmetastatic Saos-2 and metastatic derivative LM7 cells, we confirmed that dysregulation of Mcl-1 degradation and Bim induction during detachment contributes to decreased anoikis sensitivity of metastatic cells. Furthermore, knockdown of Mcl-1 or pharmacologic inhibition of the phosphoinositide-3-kinase/ Akt and mitogen-activated protein kinase pathways that suppress Mcl-1 degradation and Bim expression could markedly sensitize metastatic breast cancer cells to anoikis and prevent metastases in vivo. Therefore, Mcl-1 degradation primes the cell for Bax activation and anoikis, which can be blocked by oncogenic signaling in metastatic cells.

Original languageEnglish (US)
Pages (from-to)10744-10752
Number of pages9
JournalCancer Research
Volume67
Issue number22
DOIs
StatePublished - Nov 15 2007

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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