Differential modulation of signaling pathways and apoptosis of ras-transformed 10T1/2 cells by the depsipeptide FR901228.
(E)-(1S,4S,10S,21R)-7-[(Z)-ethylidene]-4,21-diisopropyl-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo[8,7,6]-tricos-16-ene-3,6,9,19,22-pentanone (FR901228), a natural anticancer depsipeptide, induces apoptosis of ras-transformed 10T1/2 cells whereas it induces growth arrest of nontransformed counterpart cells in G0/G1 phase of the cell cycle. Our study of the effect of FR901228 treatment on intracellular signaling pathways reveals a discriminating activity of FR901228 to regulate signaling cascades differently in ras-transformed 10T1/2 cells and nontransformed counterpart cells. Induction of apoptosis of ras-transformed cells by FR901228 correlates with suppression of the extracellular signal-regulated kinase (ERK) signaling pathway through reduction of Raf expression and deactivation of Mek and Erk, inhibition of the phosphoinositide-3 kinase (PI3-K) pathway indexed by suppression of Akt activity, suppression of p38 activity, and activation of caspase-3. Expression of p21(Cip1) is not induced in ras-transformed cultures undergoing apoptosis induced by FR901228. In contrast, FR901228 induces p21(Cip1) expression in nontransformed counterpart cultures growth-arrested in G0/G1 that is also accompanied by moderate induction of the kinase activities of Raf, Mek, Erk, and Akt, but not accompanied by activation of caspase-3 or changes in p38 activity. Our study indicates a potential value of FR901228 in the treatment of cancer cells involving aberrant regulation of Ras through preferential induction of the caspase cascade and suppression of the ERK, PI3-K, and p38 pathways.
Fecteau
Kellie A
KA
Department of Comparative Medicine, the University of Tennessee, College of Veterinary Medicine, Knoxville, Tennessee 37996, USA.
Mei
Jianxun
J
Wang
Hwa-Chain R
HC
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000235:genetics*; D015153:Blotting, Western; D042846:CDC2-CDC28 Kinases; D002452:Cell Count; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D047630:Depsipeptides; D005347:Fibroblasts; D005434:Flow Cytometry; D011905:Genes, ras / Q000235:genetics*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology; D015689:Oncogene Protein p21(ras) / Q000235:genetics; D010456:Peptides, Cyclic; D011233:Precipitin Tests; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*
D000900:Anti-Bacterial Agents; D000903:Antibiotics, Antineoplastic; D047630:Depsipeptides; D010456:Peptides, Cyclic; C087123:romidepsin; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D019950:Mitogen-Activated Protein Kinase 1; D015689:Oncogene Protein p21(ras)