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Caspases as key executors of methyl selenium-induced apoptosis (anoikis) of DU-145 prostate cancer cells.
Cancer Res. 2001 Apr 01; 61(7):3062-70.CR

Abstract

Apoptosis induction may be a mechanism mediating the anticancer activity of selenium. Our earlier work indicated that distinct cell death pathways are likely involved in apoptosis induced by the CH3SeH and the hydrogen selenide pools of selenium metabolites. To explore the role of caspases in cancer cell apoptosis induced by selenium, we examined the involvement of these molecules in the death of the DU-145 human prostate carcinoma cells induced by methylseleninic acid (MSeA), a novel penultimate precursor of the putative critical anticancer metabolite CH3SeH. Sodium selenite, a representative of the genotoxic selenium pool, was used as a reference for comparison. The results show that MSeA-induced apoptosis was accompanied by the activation of multiple caspases (caspase-3, -7, -8, and -9), mitochondrial release of cytochrome c (CC), poly(ADP-ribose) polymerase (PARP) cleavage, and DNA fragmentation. In contrast, selenite-induced apoptotic DNA fragmentation was observed in the absence of these changes, but was associated with the phosphorylation of c-Jun-NH2-terminal kinase 1/2 and p38 mitogen-activated protein kinase/stress-activated protein kinase 2. A general caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp-(OMe) fluoromethyl ketone, blocked MSeA-induced cleavage of procaspases and PARP, CC release, and DNA nucleosomal fragmentation, but did not prevent cell detachment. Furthermore, PARP cleavage and caspase activation were confined exclusively to detached cells, indicating that MSeA induction of cell detachment was a prerequisite for caspase activation and apoptosis execution. This process therefore resembled "anoikis," a special mode of apoptosis induction in which adherent cells lose contact with the extracellular matrix. Additional experiments with irreversible caspase inhibitors show that MSeA-induced anoikis involved caspase-3- and -7-mediated PARP cleavage that was initiated by caspase-8 and probably amplified through CC-caspase-9 activation and a feedback activation loop from caspase-3. Taken together, the data support a methyl selenium-specific induction of DU-145 cell apoptosis that involves cell detachment as a prerequisite (anoikis) and is executed principally through caspase-8 activation and its cross-talk with multiple caspases.

Authors+Show Affiliations

AMC Cancer Research Center, Denver, Colorado 80214, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

11306488

Citation

Jiang, C, et al. "Caspases as Key Executors of Methyl Selenium-induced Apoptosis (anoikis) of DU-145 Prostate Cancer Cells." Cancer Research, vol. 61, no. 7, 2001, pp. 3062-70.
Jiang C, Wang Z, Ganther H, et al. Caspases as key executors of methyl selenium-induced apoptosis (anoikis) of DU-145 prostate cancer cells. Cancer Res. 2001;61(7):3062-70.
Jiang, C., Wang, Z., Ganther, H., & Lu, J. (2001). Caspases as key executors of methyl selenium-induced apoptosis (anoikis) of DU-145 prostate cancer cells. Cancer Research, 61(7), 3062-70.
Jiang C, et al. Caspases as Key Executors of Methyl Selenium-induced Apoptosis (anoikis) of DU-145 Prostate Cancer Cells. Cancer Res. 2001 Apr 1;61(7):3062-70. PubMed PMID: 11306488.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Caspases as key executors of methyl selenium-induced apoptosis (anoikis) of DU-145 prostate cancer cells. AU - Jiang,C, AU - Wang,Z, AU - Ganther,H, AU - Lu,J, PY - 2001/4/18/pubmed PY - 2001/5/5/medline PY - 2001/4/18/entrez SP - 3062 EP - 70 JF - Cancer research JO - Cancer Res VL - 61 IS - 7 N2 - Apoptosis induction may be a mechanism mediating the anticancer activity of selenium. Our earlier work indicated that distinct cell death pathways are likely involved in apoptosis induced by the CH3SeH and the hydrogen selenide pools of selenium metabolites. To explore the role of caspases in cancer cell apoptosis induced by selenium, we examined the involvement of these molecules in the death of the DU-145 human prostate carcinoma cells induced by methylseleninic acid (MSeA), a novel penultimate precursor of the putative critical anticancer metabolite CH3SeH. Sodium selenite, a representative of the genotoxic selenium pool, was used as a reference for comparison. The results show that MSeA-induced apoptosis was accompanied by the activation of multiple caspases (caspase-3, -7, -8, and -9), mitochondrial release of cytochrome c (CC), poly(ADP-ribose) polymerase (PARP) cleavage, and DNA fragmentation. In contrast, selenite-induced apoptotic DNA fragmentation was observed in the absence of these changes, but was associated with the phosphorylation of c-Jun-NH2-terminal kinase 1/2 and p38 mitogen-activated protein kinase/stress-activated protein kinase 2. A general caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp-(OMe) fluoromethyl ketone, blocked MSeA-induced cleavage of procaspases and PARP, CC release, and DNA nucleosomal fragmentation, but did not prevent cell detachment. Furthermore, PARP cleavage and caspase activation were confined exclusively to detached cells, indicating that MSeA induction of cell detachment was a prerequisite for caspase activation and apoptosis execution. This process therefore resembled "anoikis," a special mode of apoptosis induction in which adherent cells lose contact with the extracellular matrix. Additional experiments with irreversible caspase inhibitors show that MSeA-induced anoikis involved caspase-3- and -7-mediated PARP cleavage that was initiated by caspase-8 and probably amplified through CC-caspase-9 activation and a feedback activation loop from caspase-3. Taken together, the data support a methyl selenium-specific induction of DU-145 cell apoptosis that involves cell detachment as a prerequisite (anoikis) and is executed principally through caspase-8 activation and its cross-talk with multiple caspases. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/11306488/Caspases_as_key_executors_of_methyl_selenium_induced_apoptosis__anoikis__of_DU_145_prostate_cancer_cells_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=11306488 DB - PRIME DP - Unbound Medicine ER -