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Selenocystine induces caspase-independent apoptosis in MCF-7 human breast carcinoma cells with involvement of p53 phosphorylation and reactive oxygen species generation.
Int J Biochem Cell Biol. 2009 Mar; 41(3):666-76.IJ

Abstract

The role of selenium as potential cancer chemopreventive and chemotherapeutic agents has been supported by epidemiological, preclinical and clinical studies. Although cell apoptosis has been evidenced as a critical mechanism mediating the anticancer activity of selenium, the underlying molecular mechanisms remain elusive. In the present study, we showed that selenocystine (SeC), a naturally occurring selenoamino acid, induced caspase-independent apoptosis in MCF-7 breast carcinoma cells, which was accompanied by poly(ADP-ribose) polymerase (PARP) cleavage, caspase activation, DNA fragmentation, phosphatidylserine exposure and nuclear condensation. Moreover, SeC induced the loss of mitochondrial membrane potential (DeltaPsi(m)) by regulating the expression and phosphorylation of Bcl-2 family members. Loss of DeltaPsi(m) led to the mitochondrial release of cytochrome c and apoptosis-inducing factor (AIF) which subsequently translocated into the nucleus and induced chromatin condensation and DNA fragmentation. MCF-7 cells exposed to SeC shown increase in total p53 and phosphorylated p53 on serine residues of Ser15, Ser20, and Ser392 prior to mitochondrial dysfunction. Silencing and attenuating of p53 activation with RNA interference and pifithrin-alpha treatment, respectively, partially suppressed SeC-induced cell apoptosis. Furthermore, generation of reactive oxygen species and subsequent induction of DNA strand breaks were found to be upstream cellular events induced by SeC. The thiol-reducing antioxidants, N-acetylcysteine and glutathione, completely blocked the occurrence of cell apoptosis. Taken together, these results suggest that SeC, as a promising anticancer selenocompound, induces MCF-7 cell apoptosis by activating ROS-mediated mitochondrial pathway and p53 phosphorylation.

Authors+Show Affiliations

Department of Biology, The Chinese University of Hong Kong, Hong Kong SAR, China.No affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

18718551

Citation

Chen, Tianfeng, and Yum-Shing Wong. "Selenocystine Induces Caspase-independent Apoptosis in MCF-7 Human Breast Carcinoma Cells With Involvement of P53 Phosphorylation and Reactive Oxygen Species Generation." The International Journal of Biochemistry & Cell Biology, vol. 41, no. 3, 2009, pp. 666-76.
Chen T, Wong YS. Selenocystine induces caspase-independent apoptosis in MCF-7 human breast carcinoma cells with involvement of p53 phosphorylation and reactive oxygen species generation. Int J Biochem Cell Biol. 2009;41(3):666-76.
Chen, T., & Wong, Y. S. (2009). Selenocystine induces caspase-independent apoptosis in MCF-7 human breast carcinoma cells with involvement of p53 phosphorylation and reactive oxygen species generation. The International Journal of Biochemistry & Cell Biology, 41(3), 666-76. https://doi.org/10.1016/j.biocel.2008.07.014
Chen T, Wong YS. Selenocystine Induces Caspase-independent Apoptosis in MCF-7 Human Breast Carcinoma Cells With Involvement of P53 Phosphorylation and Reactive Oxygen Species Generation. Int J Biochem Cell Biol. 2009;41(3):666-76. PubMed PMID: 18718551.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Selenocystine induces caspase-independent apoptosis in MCF-7 human breast carcinoma cells with involvement of p53 phosphorylation and reactive oxygen species generation. AU - Chen,Tianfeng, AU - Wong,Yum-Shing, Y1 - 2008/08/05/ PY - 2008/06/04/received PY - 2008/07/12/revised PY - 2008/07/22/accepted PY - 2008/8/23/pubmed PY - 2009/12/16/medline PY - 2008/8/23/entrez SP - 666 EP - 76 JF - The international journal of biochemistry & cell biology JO - Int J Biochem Cell Biol VL - 41 IS - 3 N2 - The role of selenium as potential cancer chemopreventive and chemotherapeutic agents has been supported by epidemiological, preclinical and clinical studies. Although cell apoptosis has been evidenced as a critical mechanism mediating the anticancer activity of selenium, the underlying molecular mechanisms remain elusive. In the present study, we showed that selenocystine (SeC), a naturally occurring selenoamino acid, induced caspase-independent apoptosis in MCF-7 breast carcinoma cells, which was accompanied by poly(ADP-ribose) polymerase (PARP) cleavage, caspase activation, DNA fragmentation, phosphatidylserine exposure and nuclear condensation. Moreover, SeC induced the loss of mitochondrial membrane potential (DeltaPsi(m)) by regulating the expression and phosphorylation of Bcl-2 family members. Loss of DeltaPsi(m) led to the mitochondrial release of cytochrome c and apoptosis-inducing factor (AIF) which subsequently translocated into the nucleus and induced chromatin condensation and DNA fragmentation. MCF-7 cells exposed to SeC shown increase in total p53 and phosphorylated p53 on serine residues of Ser15, Ser20, and Ser392 prior to mitochondrial dysfunction. Silencing and attenuating of p53 activation with RNA interference and pifithrin-alpha treatment, respectively, partially suppressed SeC-induced cell apoptosis. Furthermore, generation of reactive oxygen species and subsequent induction of DNA strand breaks were found to be upstream cellular events induced by SeC. The thiol-reducing antioxidants, N-acetylcysteine and glutathione, completely blocked the occurrence of cell apoptosis. Taken together, these results suggest that SeC, as a promising anticancer selenocompound, induces MCF-7 cell apoptosis by activating ROS-mediated mitochondrial pathway and p53 phosphorylation. SN - 1878-5875 UR - https://www.unboundmedicine.com/medline/citation/18718551/Selenocystine_induces_caspase_independent_apoptosis_in_MCF_7_human_breast_carcinoma_cells_with_involvement_of_p53_phosphorylation_and_reactive_oxygen_species_generation_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1357-2725(08)00315-4 DB - PRIME DP - Unbound Medicine ER -