Differential apoptotic response of human cancer cells to organoselenium compounds

Maiko Suzuki, Manabu Endo, Fumiaki Shinohara, Seishi Echigo, Hidemi Rikiishi

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

Purpose: Selenium (Se) compounds are well known to inhibit cell proliferation and induce cell death in human cancer cells. Respective chemical forms of Se are intracellularly metabolized via complicated pathways, which target distinct molecules and exhibit varying degrees of anti-carcinogenicity in different cancer types; however, the precise mechanisms by which Se activates apoptosis remain poorly understood. Methods: The effects of Se compounds, Se-methylselenocysteine (MSC), selenomethionine (SeMet), and selenite on cell proliferation, apoptosis and its pathway in established human carcinoma cell lines (HSC-3,-4, A549, and MCF-7) were investigated. Cancer cells were treated with each Se compound during different periods. Cell apoptosis, caspase activity and ER stress markers were analyzed by flow cytometric or immunoblotting analysis, respectively. Results: We examined four cell lines for their sensitivity to MSC and SeMet in comparison with selenite. SeMet increased apoptotic cells in p53-positive A549 cells, whereas MSC increased apoptotic cells in p53-mutated HSC-3 cells. High activities of caspase-3,-8 and-9 were observed during apoptosis, and a pan-caspase inhibitor, z-VAD-fmk, rescued the cell viability of HSC-3 cells exposed to MSC. In addition, the occurrence of endoplasmic reticulum (ER) stress was suggested by the observation that levels of phosphorylated eIF2α and caspase-12 activity are increased in Se-treated cells. Selenite and MSC were accompanied with the concurrent reduction of phosphorylated Akt levels, and the inhibitory effects of these Se compounds on vascular endothelial growth factor expression were observed with identical patterns. Conclusion: The present findings demonstrate that Seinduced apoptosis in carcinoma cells is basically a caspasedependent process involving complicated mechanisms. Activation of both the intrinsic apoptotic pathway and ER stress pathway plays a major and concurrent role, while p53 activation seems to have only a functional role in SeMet.

Original languageEnglish (US)
Pages (from-to)475-484
Number of pages10
JournalCancer Chemotherapy and Pharmacology
Volume66
Issue number3
DOIs
StatePublished - Aug 1 2010
Externally publishedYes

Fingerprint

Organoselenium Compounds
Cells
Selenium Compounds
Selenomethionine
Selenium
Selenious Acid
Neoplasms
Endoplasmic Reticulum Stress
Apoptosis
Cell proliferation
Caspase 12
Chemical activation
Cell Proliferation
Carcinoma
Cell Line
Caspase Inhibitors
Caspase 8
Cell death
Caspases
Immunoblotting

Keywords

  • Angiogenesis
  • Apoptosis
  • Caspase-12
  • Endoplasmic reticulum stress
  • Organoselenium compounds
  • p53

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Toxicology

Cite this

Differential apoptotic response of human cancer cells to organoselenium compounds. / Suzuki, Maiko; Endo, Manabu; Shinohara, Fumiaki; Echigo, Seishi; Rikiishi, Hidemi.

In: Cancer Chemotherapy and Pharmacology, Vol. 66, No. 3, 01.08.2010, p. 475-484.

Research output: Contribution to journalArticle

Suzuki, Maiko ; Endo, Manabu ; Shinohara, Fumiaki ; Echigo, Seishi ; Rikiishi, Hidemi. / Differential apoptotic response of human cancer cells to organoselenium compounds. In: Cancer Chemotherapy and Pharmacology. 2010 ; Vol. 66, No. 3. pp. 475-484.
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T1 - Differential apoptotic response of human cancer cells to organoselenium compounds

AU - Suzuki, Maiko

AU - Endo, Manabu

AU - Shinohara, Fumiaki

AU - Echigo, Seishi

AU - Rikiishi, Hidemi

PY - 2010/8/1

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N2 - Purpose: Selenium (Se) compounds are well known to inhibit cell proliferation and induce cell death in human cancer cells. Respective chemical forms of Se are intracellularly metabolized via complicated pathways, which target distinct molecules and exhibit varying degrees of anti-carcinogenicity in different cancer types; however, the precise mechanisms by which Se activates apoptosis remain poorly understood. Methods: The effects of Se compounds, Se-methylselenocysteine (MSC), selenomethionine (SeMet), and selenite on cell proliferation, apoptosis and its pathway in established human carcinoma cell lines (HSC-3,-4, A549, and MCF-7) were investigated. Cancer cells were treated with each Se compound during different periods. Cell apoptosis, caspase activity and ER stress markers were analyzed by flow cytometric or immunoblotting analysis, respectively. Results: We examined four cell lines for their sensitivity to MSC and SeMet in comparison with selenite. SeMet increased apoptotic cells in p53-positive A549 cells, whereas MSC increased apoptotic cells in p53-mutated HSC-3 cells. High activities of caspase-3,-8 and-9 were observed during apoptosis, and a pan-caspase inhibitor, z-VAD-fmk, rescued the cell viability of HSC-3 cells exposed to MSC. In addition, the occurrence of endoplasmic reticulum (ER) stress was suggested by the observation that levels of phosphorylated eIF2α and caspase-12 activity are increased in Se-treated cells. Selenite and MSC were accompanied with the concurrent reduction of phosphorylated Akt levels, and the inhibitory effects of these Se compounds on vascular endothelial growth factor expression were observed with identical patterns. Conclusion: The present findings demonstrate that Seinduced apoptosis in carcinoma cells is basically a caspasedependent process involving complicated mechanisms. Activation of both the intrinsic apoptotic pathway and ER stress pathway plays a major and concurrent role, while p53 activation seems to have only a functional role in SeMet.

AB - Purpose: Selenium (Se) compounds are well known to inhibit cell proliferation and induce cell death in human cancer cells. Respective chemical forms of Se are intracellularly metabolized via complicated pathways, which target distinct molecules and exhibit varying degrees of anti-carcinogenicity in different cancer types; however, the precise mechanisms by which Se activates apoptosis remain poorly understood. Methods: The effects of Se compounds, Se-methylselenocysteine (MSC), selenomethionine (SeMet), and selenite on cell proliferation, apoptosis and its pathway in established human carcinoma cell lines (HSC-3,-4, A549, and MCF-7) were investigated. Cancer cells were treated with each Se compound during different periods. Cell apoptosis, caspase activity and ER stress markers were analyzed by flow cytometric or immunoblotting analysis, respectively. Results: We examined four cell lines for their sensitivity to MSC and SeMet in comparison with selenite. SeMet increased apoptotic cells in p53-positive A549 cells, whereas MSC increased apoptotic cells in p53-mutated HSC-3 cells. High activities of caspase-3,-8 and-9 were observed during apoptosis, and a pan-caspase inhibitor, z-VAD-fmk, rescued the cell viability of HSC-3 cells exposed to MSC. In addition, the occurrence of endoplasmic reticulum (ER) stress was suggested by the observation that levels of phosphorylated eIF2α and caspase-12 activity are increased in Se-treated cells. Selenite and MSC were accompanied with the concurrent reduction of phosphorylated Akt levels, and the inhibitory effects of these Se compounds on vascular endothelial growth factor expression were observed with identical patterns. Conclusion: The present findings demonstrate that Seinduced apoptosis in carcinoma cells is basically a caspasedependent process involving complicated mechanisms. Activation of both the intrinsic apoptotic pathway and ER stress pathway plays a major and concurrent role, while p53 activation seems to have only a functional role in SeMet.

KW - Angiogenesis

KW - Apoptosis

KW - Caspase-12

KW - Endoplasmic reticulum stress

KW - Organoselenium compounds

KW - p53

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