Abstract
(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 ofras-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 p21Cip1 is not induced inras-transformed cultures undergoing apoptosis induced by FR901228. In contrast, FR901228 induces p21Cip1expression 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.
Footnotes
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This research was supported mainly by Grant 1R29CA69530 from the National Institutes of Health and the University of Tennessee Center of Excellence Fund (to H.-C.R.W.), and initially and partly by contract CM57201 from the National Cancer Institute (K.K.C.). The work was previously presented in the 92nd Annual AACR Meeting. Experimental/Molecular Therapeutics 11, No. 1113. The abstract was published in the Proceedings of the America Association for Cancer Research; 2001 Mar 24–28; New Orleans, LA. Vol 42, pp 208, American Association for Cancer Research, Philadelphia, PA.
- Abbreviations:
- FR901228 (NSC-630176)
- (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
- ERK
- extracellular signal-regulated kinase
- PI3-K
- phosphoinositide-3 kinase
- JNK
- c-Jun NH2-terminal kinase
- GST-RBD
- glutathione transferase-fused Ras-binding domain
- MBP
- myelin basic protein
- TUNEL
- terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick-end labeling
- Received October 16, 2001.
- Accepted December 4, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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