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Titolo:
Constitutively active Akt is an important regulator of TRAIL sensitivity in prostate cancer
Autore:
Chen, XF; Thakkar, H; Tyan, F; Gim, S; Robinson, H; Lee, C; Pandey, SK; Nwokorie, C; Onwudiwe, N; Srivastava, RK;
Indirizzi:
Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Greenebaum Canc Ctr, Baltimore, MD 21201 USA Univ Maryland Baltimore MD USA 21201 um Canc Ctr, Baltimore, MD 21201 USA NIA, Clin Invest Lab, NIH, Baltimore, MD 21224 USA NIA Baltimore MD USA 21224 Clin Invest Lab, NIH, Baltimore, MD 21224 USA
Titolo Testata:
ONCOGENE
fascicolo: 42, volume: 20, anno: 2001,
pagine: 6073 - 6083
SICI:
0950-9232(20010920)20:42<6073:CAAIAI>2.0.ZU;2-P
Fonte:
ISI
Lingua:
ENG
Soggetto:
PROTEIN-KINASE-B; FORKHEAD TRANSCRIPTION FACTORS; INDUCED APOPTOSIS; TUMOR-SUPPRESSOR; CYTOCHROME-C; CELL-DEATH; FREQUENT INACTIVATION; TUMORICIDAL ACTIVITY; NEGATIVE REGULATION; SURVIVAL SIGNALS;
Keywords:
TRAIL; apoptosis; prostate cancer; mitochondria; Akt; PTEN;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
87
Recensione:
Indirizzi per estratti:
Indirizzo: Srivastava, RK Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Greenebaum Canc Ctr, 20 N Pine St, Baltimore, MD 21201 USA Univ Maryland 20 N Pine St Baltimore MD USA 21201 21201 USA
Citazione:
X.F. Chen et al., "Constitutively active Akt is an important regulator of TRAIL sensitivity in prostate cancer", ONCOGENE, 20(42), 2001, pp. 6073-6083

Abstract

TRAIL/Apo-2L is a member of the tumor necrosis factor superfamily and has recently been shown to induce apoptosis in cancer cells, but not in normal cells. In nude mice injected with human tumors, TRAIL reduces the size of these tumors without side effects. Akt promotes cell survival and block apoptosis. Some prostate cancer cells express high levels of Akt due to lack ofactive lipid phosphatase PTEN, a negative regulator of PI-3 kinase pathway, which may be responsible for drug resistance. The objective of this paperis to investigate the intracellular molecules that regulate TRAIL resistance. We have examined caspase-8 activity, BID cleavage, Akt activity, mitochondrial membrane potential (AT.) and apoptosis in prostate cancer (LNCap, PC-3, PC-3M and DU145) cells treated with or without TRAIL. PC-3, PC-3M and DU145 cells are sensitive to TRAIL, whereas LNCap cells are resistant. LNCap cells express the highest level of constitutively active Akt, which is directly correlated with TRAIL resistance. TRAIL activates caspase-8 in all the cell lines. Downregulation of constitutively active Akt by PI-3 kinase inhibitors (wortmannin and LY-294002), dominant negative Akt or PTEN, renders LNCap cells sensitive to TRAIL. Inhibition of TRAIL sensitivity occurs atthe level of BID cleavage. Inhibition of protein synthesis by cycloheximide also causes LNCap cells sensitive to TRAIL. Overexpression of Bcl-2 or Bcl-X-L inhibits TRAIL-induced Delta Psi (m) and apoptosis. Overexpression ofconstitutively active Akt in PC-3M cells (express very low levels of constitutively active Akt) restores TRAIL resistance. These data suggest that elevated Akt activity protects LNCap cells from TRAIL-induced apoptosis, and the PI-3 kinase/Akt pathway may inhibit apoptotic signals by inhibiting processing of BID. Thus, constitutively active Akt is an important regulator of TRAIL sensitivity in prostate cancer.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 28/09/20 alle ore 02:23:30