Key roles of BIM-driven apoptosis in epithelial tumors and rational chemotherapy.
Defective apoptosis not only promotes tumorigenesis, but also can confound chemotherapeutic response. Here we demonstrate that the proapoptotic BH3-only protein BIM is a tumor suppressor in epithelial solid tumors and also is a determinant in paclitaxel sensitivity in vivo. Furthermore, the H-ras/mitogen-activated protein kinase (MAPK) pathway conferred resistance to paclitaxel that was dependent on functional inactivation of BIM. Whereas paclitaxel induced BIM accumulation and BIM-dependent apoptosis in vitro and in tumors in vivo, the H-ras/MAPK pathway suppressed this BIM induction by phosphorylating BIM and targeting BIM for degradation in proteasomes. The proteasome inhibitor Velcade (P-341, Bortezomib) restored BIM induction, abrogated H-ras-dependent paclitaxel resistance, and promoted BIM-dependent tumor regression, suggesting the potential benefits of combinatorial chemotherapy of Velcade and paclitaxel.
Tan
Ting-Ting
TT
Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey 08854, USA.
Degenhardt
Kurt
K
Nelson
Deirdre A
DA
Beaudoin
Brian
B
Nieves-Neira
Wilberto
W
Bouillet
Philippe
P
Villunger
Andreas
A
Adams
Jerry M
JM
White
Eileen
E
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism / Q000627:therapeutic use*; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D001897:Boronic Acids / Q000627:therapeutic use; D000069286:Bortezomib; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D019008:Drug Resistance, Neoplasm; D004359:Drug Therapy, Combination; D005786:Gene Expression Regulation; D011905:Genes, ras; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000378:metabolism*; D017239:Paclitaxel / Q000378:metabolism / Q000627:therapeutic use*; D011480:Protease Inhibitors / Q000627:therapeutic use; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011719:Pyrazines / Q000627:therapeutic use; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D001897:Boronic Acids; D002352:Carrier Proteins; D008565:Membrane Proteins; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011518:Proto-Oncogene Proteins; D011719:Pyrazines; D016159:Tumor Suppressor Protein p53; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex; D017239:Paclitaxel