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

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.

• Authors: Nicholas T Woods, Hirohito Yamaguchi, Francis Y Lee, Kapil N Bhalla, Hong-Gang Wang
• Journal: Cancer research (Cancer Res) Vol. 67 Issue 22 Pg. 10744-52 (Nov 15 2007) ISSN: 1538-7445 [Electronic] United States
• PMID: 18006817 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• 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)