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

Cancer Res. 2007 Nov 15;67(22):10744-52. doi: 10.1158/0008-5472.CAN-07-3148.

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-3beta-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anoikis*
  • Apoptosis Regulatory Proteins / biosynthesis*
  • Bcl-2-Like Protein 11
  • Caspase 3 / metabolism
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic*
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • L-Lactate Dehydrogenase / metabolism
  • Membrane Proteins / biosynthesis*
  • Mice
  • Myeloid Cell Leukemia Sequence 1 Protein
  • NIH 3T3 Cells
  • Neoplasm Metastasis
  • Neoplasm Proteins / biosynthesis*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins / biosynthesis*
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis*
  • bcl-2-Associated X Protein / metabolism

Substances

  • Apoptosis Regulatory Proteins
  • BCL2L11 protein, human
  • Bcl-2-Like Protein 11
  • Bcl2l11 protein, mouse
  • Mcl1 protein, mouse
  • Membrane Proteins
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-2-Associated X Protein
  • L-Lactate Dehydrogenase
  • Phosphatidylinositol 3-Kinases
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Glycogen Synthase Kinase 3
  • Caspase 3