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      1. Author :
        Woods, Nicholas T; Yamaguchi, Hirohito; Lee, Francis Y; Bhalla, Kapil N; Wang, Hong-Gang
      2. Title :
      3. Type :
        Journal Article
      4. Year :
      5. Publication :
        Cancer research
      6. Products :
      7. Volume :
      8. Issue :
      9. Page Numbers :
      10. Research Area :
      11. Keywords :
        Animals; Anoikis; Apoptosis Regulatory Proteins; bcl-2-Associated X Protein; Bioware; Caspase 3; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Glycogen Synthase Kinase 3; Humans; L-Lactate Dehydrogenase; MDA-MB-231-D3H2LN cells; Membrane Proteins; Mice; Neoplasm Metastasis; Neoplasm Proteins; NIH 3T3 Cells; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2
      12. 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.
      13. URL :
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :