Anoikis, initiated by Mcl-1 degradation and Bim induction, is deregulated during oncogenesis.
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.
Woods
Nicholas T
NT
H. Lee Moffitt Cancer Center & Research Institute, University of South Florida, Tampa, Florida 33612, USA.
Yamaguchi
Hirohito
H
Lee
Francis Y
FY
Bhalla
Kapil N
KN
Wang
Hong-Gang
HG
D000818:Animals; D023102:Anoikis; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis*; D000072224:Bcl-2-Like Protein 11; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008565:Membrane Proteins / Q000096:biosynthesis*; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D041681:NIH 3T3 Cells; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C579094:Mcl1 protein, mouse; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D007770:L-Lactate Dehydrogenase; D019869:Phosphatidylinositol 3-Kinases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D053148:Caspase 3