Downregulation of c-Myc determines sensitivity to 2-methoxyestradiol-induced apoptosis in human acute myeloid leukemia

Jyh-Ming Chow, Chien Ru Liu, Che Pin Lin, Chun Nin Lee, Yun Chih Cheng, Shufan Lin, Hsingjin-Eugene Liu

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Objective: 2-Methoxyestradiol (2ME2) has been shown to induce apoptosis in leukemic cells, but its exact mechanism remains unclear. Because c-Myc plays a critical role in leukemogenesis, we evaluated whether 2ME2 acts on acute myeloid leukemia (AML) through modulation of c-Myc activity. Materials and Methods: AML cell lines and primary AML leukemia were treated with 2ME2 and the relationship between 2ME2-induced apoptosis and changes in c-Myc activity was examined. Results: 2ME2 induced mitochondrial apoptosis of human AML cells through increased reactive oxygen species. Further investigation showed that 2ME2 downregulated c-Myc expression in a time-dependent manner. Increased oxidative stress led to downregulation of c-Myc mRNA and protein, but did not affect the stability of c-Myc protein. To demonstrate the role of c-Myc in 2ME2-induced apoptosis, we ectopically expressed wild-type c-Myc in AML cells and found that ectopic expression of c-Myc abrogated the 2ME2-induced apoptosis. In addition, we showed that 2ME2 treatment inhibited phosphorylation of Akt and binding of nuclear factor-κB p65/p50 heterodimers to its DNA targets. As with results from cell lines studied, 2ME2 also induced cytotoxicity to primary AML cells and downregulated their c-Myc expression and induced apoptosis. Conclusion: Downregulation of c-Myc is critical for 2ME2-induced oxidative stress and apoptosis in AML cells. Our results might be extended to other types of cancers overexpressing c-Myc.

Original languageEnglish
Pages (from-to)140-148
Number of pages9
JournalExperimental Hematology
Volume36
Issue number2
DOIs
Publication statusPublished - Feb 2008

Fingerprint

Acute Myeloid Leukemia
Down-Regulation
Myeloid Cells
Apoptosis
Proto-Oncogene Proteins c-myc
Oxidative Stress
Cell Line
2-methoxyestradiol
Reactive Oxygen Species
Leukemia
Phosphorylation
Messenger RNA
DNA
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Genetics
  • Hematology
  • Oncology
  • Transplantation

Cite this

Downregulation of c-Myc determines sensitivity to 2-methoxyestradiol-induced apoptosis in human acute myeloid leukemia. / Chow, Jyh-Ming; Liu, Chien Ru; Lin, Che Pin; Lee, Chun Nin; Cheng, Yun Chih; Lin, Shufan; Liu, Hsingjin-Eugene.

In: Experimental Hematology, Vol. 36, No. 2, 02.2008, p. 140-148.

Research output: Contribution to journalArticle

Chow, Jyh-Ming ; Liu, Chien Ru ; Lin, Che Pin ; Lee, Chun Nin ; Cheng, Yun Chih ; Lin, Shufan ; Liu, Hsingjin-Eugene. / Downregulation of c-Myc determines sensitivity to 2-methoxyestradiol-induced apoptosis in human acute myeloid leukemia. In: Experimental Hematology. 2008 ; Vol. 36, No. 2. pp. 140-148.
@article{724a9719afcf47cea2eef18352a54aeb,
title = "Downregulation of c-Myc determines sensitivity to 2-methoxyestradiol-induced apoptosis in human acute myeloid leukemia",
abstract = "Objective: 2-Methoxyestradiol (2ME2) has been shown to induce apoptosis in leukemic cells, but its exact mechanism remains unclear. Because c-Myc plays a critical role in leukemogenesis, we evaluated whether 2ME2 acts on acute myeloid leukemia (AML) through modulation of c-Myc activity. Materials and Methods: AML cell lines and primary AML leukemia were treated with 2ME2 and the relationship between 2ME2-induced apoptosis and changes in c-Myc activity was examined. Results: 2ME2 induced mitochondrial apoptosis of human AML cells through increased reactive oxygen species. Further investigation showed that 2ME2 downregulated c-Myc expression in a time-dependent manner. Increased oxidative stress led to downregulation of c-Myc mRNA and protein, but did not affect the stability of c-Myc protein. To demonstrate the role of c-Myc in 2ME2-induced apoptosis, we ectopically expressed wild-type c-Myc in AML cells and found that ectopic expression of c-Myc abrogated the 2ME2-induced apoptosis. In addition, we showed that 2ME2 treatment inhibited phosphorylation of Akt and binding of nuclear factor-κB p65/p50 heterodimers to its DNA targets. As with results from cell lines studied, 2ME2 also induced cytotoxicity to primary AML cells and downregulated their c-Myc expression and induced apoptosis. Conclusion: Downregulation of c-Myc is critical for 2ME2-induced oxidative stress and apoptosis in AML cells. Our results might be extended to other types of cancers overexpressing c-Myc.",
author = "Jyh-Ming Chow and Liu, {Chien Ru} and Lin, {Che Pin} and Lee, {Chun Nin} and Cheng, {Yun Chih} and Shufan Lin and Hsingjin-Eugene Liu",
year = "2008",
month = "2",
doi = "10.1016/j.exphem.2007.10.004",
language = "English",
volume = "36",
pages = "140--148",
journal = "Experimental Hematology",
issn = "0301-472X",
publisher = "Elsevier Inc.",
number = "2",

}

TY - JOUR

T1 - Downregulation of c-Myc determines sensitivity to 2-methoxyestradiol-induced apoptosis in human acute myeloid leukemia

AU - Chow, Jyh-Ming

AU - Liu, Chien Ru

AU - Lin, Che Pin

AU - Lee, Chun Nin

AU - Cheng, Yun Chih

AU - Lin, Shufan

AU - Liu, Hsingjin-Eugene

PY - 2008/2

Y1 - 2008/2

N2 - Objective: 2-Methoxyestradiol (2ME2) has been shown to induce apoptosis in leukemic cells, but its exact mechanism remains unclear. Because c-Myc plays a critical role in leukemogenesis, we evaluated whether 2ME2 acts on acute myeloid leukemia (AML) through modulation of c-Myc activity. Materials and Methods: AML cell lines and primary AML leukemia were treated with 2ME2 and the relationship between 2ME2-induced apoptosis and changes in c-Myc activity was examined. Results: 2ME2 induced mitochondrial apoptosis of human AML cells through increased reactive oxygen species. Further investigation showed that 2ME2 downregulated c-Myc expression in a time-dependent manner. Increased oxidative stress led to downregulation of c-Myc mRNA and protein, but did not affect the stability of c-Myc protein. To demonstrate the role of c-Myc in 2ME2-induced apoptosis, we ectopically expressed wild-type c-Myc in AML cells and found that ectopic expression of c-Myc abrogated the 2ME2-induced apoptosis. In addition, we showed that 2ME2 treatment inhibited phosphorylation of Akt and binding of nuclear factor-κB p65/p50 heterodimers to its DNA targets. As with results from cell lines studied, 2ME2 also induced cytotoxicity to primary AML cells and downregulated their c-Myc expression and induced apoptosis. Conclusion: Downregulation of c-Myc is critical for 2ME2-induced oxidative stress and apoptosis in AML cells. Our results might be extended to other types of cancers overexpressing c-Myc.

AB - Objective: 2-Methoxyestradiol (2ME2) has been shown to induce apoptosis in leukemic cells, but its exact mechanism remains unclear. Because c-Myc plays a critical role in leukemogenesis, we evaluated whether 2ME2 acts on acute myeloid leukemia (AML) through modulation of c-Myc activity. Materials and Methods: AML cell lines and primary AML leukemia were treated with 2ME2 and the relationship between 2ME2-induced apoptosis and changes in c-Myc activity was examined. Results: 2ME2 induced mitochondrial apoptosis of human AML cells through increased reactive oxygen species. Further investigation showed that 2ME2 downregulated c-Myc expression in a time-dependent manner. Increased oxidative stress led to downregulation of c-Myc mRNA and protein, but did not affect the stability of c-Myc protein. To demonstrate the role of c-Myc in 2ME2-induced apoptosis, we ectopically expressed wild-type c-Myc in AML cells and found that ectopic expression of c-Myc abrogated the 2ME2-induced apoptosis. In addition, we showed that 2ME2 treatment inhibited phosphorylation of Akt and binding of nuclear factor-κB p65/p50 heterodimers to its DNA targets. As with results from cell lines studied, 2ME2 also induced cytotoxicity to primary AML cells and downregulated their c-Myc expression and induced apoptosis. Conclusion: Downregulation of c-Myc is critical for 2ME2-induced oxidative stress and apoptosis in AML cells. Our results might be extended to other types of cancers overexpressing c-Myc.

UR - http://www.scopus.com/inward/record.url?scp=38149042802&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=38149042802&partnerID=8YFLogxK

U2 - 10.1016/j.exphem.2007.10.004

DO - 10.1016/j.exphem.2007.10.004

M3 - Article

C2 - 18206725

AN - SCOPUS:38149042802

VL - 36

SP - 140

EP - 148

JO - Experimental Hematology

JF - Experimental Hematology

SN - 0301-472X

IS - 2

ER -