Shikonin induces cell cycle arrest in human gastric cancer (AGS) by early growth response 1 (Egr1)-mediated p21 gene expression

Sun Joong Kim, Jee Min Kim, So Hee Shim, Hyo-Ihl Chang

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Ethnopharmacological relevance Lithospermum erythrorhizon, a naphthoquinone compound derived from a shikonin, has long been used as traditional Chinese medicine for treatment of various diseases, including cancer. To evaluate the cytotoxic effects of shikonin on AGS gastric cancer cells via induction of cell cycle arrest. Materials and methods We observed the effects of 12.5-100 ng/mL dosage of shikonin treatment on AGS cancer cell line with the incubation time of 6 h. Cytotoxic effects were assessed by measuring the changes in the intracellular ROS, appearance of senescence phenotype, cell cycle progression, CDK and cyclins expression levels upon shikonin treatment. We also examined upon the activation of Egr1-mediated p21 expression, by siRNA transfection, Luciferase assay, and ChIP assay. Results In this study, we found that shikonin inhibits cell proliferation by arresting cell cycle progression at the G2/M phase via modulation of p21 in AGS cells. Also, our results revealed that the p21 gene was transactivated by early growth response1 (Egr1) in response to the shikonin treatment. Transient Egr1 expression enhanced shikonin-induced p21 promoter activity, whereas the suppression of Egr1 expression by small interfering RNA attenuated the ability of shikonin to induce p21 promoter activity. Conclusion Our results suggested that the anti-proliferative activity of shikonin was due to its ability to induce cell cycle arrest via Egr1-p21 signaling pathway. Thus, the work stated here validates the traditional use of shikonin in the treatment of cancer.

Original languageEnglish
Pages (from-to)1064-1071
Number of pages8
JournalJournal of Ethnopharmacology
Volume151
Issue number3
DOIs
Publication statusPublished - 2014 Feb 12

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Cell Cycle Checkpoints
Stomach Neoplasms
Gene Expression
Growth
Small Interfering RNA
Cell Cycle
Lithospermum
shikonin
Naphthoquinones
Therapeutics
Neoplasms
Cyclins
G2 Phase
Chinese Traditional Medicine
Luciferases
Cell Division
Transfection
Cell Proliferation
Phenotype
Cell Line

Keywords

  • Anti-proliferation
  • Cell cycle arrest
  • Egr1
  • p21
  • Shikonin

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery

Cite this

Shikonin induces cell cycle arrest in human gastric cancer (AGS) by early growth response 1 (Egr1)-mediated p21 gene expression. / Kim, Sun Joong; Kim, Jee Min; Shim, So Hee; Chang, Hyo-Ihl.

In: Journal of Ethnopharmacology, Vol. 151, No. 3, 12.02.2014, p. 1064-1071.

Research output: Contribution to journalArticle

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abstract = "Ethnopharmacological relevance Lithospermum erythrorhizon, a naphthoquinone compound derived from a shikonin, has long been used as traditional Chinese medicine for treatment of various diseases, including cancer. To evaluate the cytotoxic effects of shikonin on AGS gastric cancer cells via induction of cell cycle arrest. Materials and methods We observed the effects of 12.5-100 ng/mL dosage of shikonin treatment on AGS cancer cell line with the incubation time of 6 h. Cytotoxic effects were assessed by measuring the changes in the intracellular ROS, appearance of senescence phenotype, cell cycle progression, CDK and cyclins expression levels upon shikonin treatment. We also examined upon the activation of Egr1-mediated p21 expression, by siRNA transfection, Luciferase assay, and ChIP assay. Results In this study, we found that shikonin inhibits cell proliferation by arresting cell cycle progression at the G2/M phase via modulation of p21 in AGS cells. Also, our results revealed that the p21 gene was transactivated by early growth response1 (Egr1) in response to the shikonin treatment. Transient Egr1 expression enhanced shikonin-induced p21 promoter activity, whereas the suppression of Egr1 expression by small interfering RNA attenuated the ability of shikonin to induce p21 promoter activity. Conclusion Our results suggested that the anti-proliferative activity of shikonin was due to its ability to induce cell cycle arrest via Egr1-p21 signaling pathway. Thus, the work stated here validates the traditional use of shikonin in the treatment of cancer.",
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N2 - Ethnopharmacological relevance Lithospermum erythrorhizon, a naphthoquinone compound derived from a shikonin, has long been used as traditional Chinese medicine for treatment of various diseases, including cancer. To evaluate the cytotoxic effects of shikonin on AGS gastric cancer cells via induction of cell cycle arrest. Materials and methods We observed the effects of 12.5-100 ng/mL dosage of shikonin treatment on AGS cancer cell line with the incubation time of 6 h. Cytotoxic effects were assessed by measuring the changes in the intracellular ROS, appearance of senescence phenotype, cell cycle progression, CDK and cyclins expression levels upon shikonin treatment. We also examined upon the activation of Egr1-mediated p21 expression, by siRNA transfection, Luciferase assay, and ChIP assay. Results In this study, we found that shikonin inhibits cell proliferation by arresting cell cycle progression at the G2/M phase via modulation of p21 in AGS cells. Also, our results revealed that the p21 gene was transactivated by early growth response1 (Egr1) in response to the shikonin treatment. Transient Egr1 expression enhanced shikonin-induced p21 promoter activity, whereas the suppression of Egr1 expression by small interfering RNA attenuated the ability of shikonin to induce p21 promoter activity. Conclusion Our results suggested that the anti-proliferative activity of shikonin was due to its ability to induce cell cycle arrest via Egr1-p21 signaling pathway. Thus, the work stated here validates the traditional use of shikonin in the treatment of cancer.

AB - Ethnopharmacological relevance Lithospermum erythrorhizon, a naphthoquinone compound derived from a shikonin, has long been used as traditional Chinese medicine for treatment of various diseases, including cancer. To evaluate the cytotoxic effects of shikonin on AGS gastric cancer cells via induction of cell cycle arrest. Materials and methods We observed the effects of 12.5-100 ng/mL dosage of shikonin treatment on AGS cancer cell line with the incubation time of 6 h. Cytotoxic effects were assessed by measuring the changes in the intracellular ROS, appearance of senescence phenotype, cell cycle progression, CDK and cyclins expression levels upon shikonin treatment. We also examined upon the activation of Egr1-mediated p21 expression, by siRNA transfection, Luciferase assay, and ChIP assay. Results In this study, we found that shikonin inhibits cell proliferation by arresting cell cycle progression at the G2/M phase via modulation of p21 in AGS cells. Also, our results revealed that the p21 gene was transactivated by early growth response1 (Egr1) in response to the shikonin treatment. Transient Egr1 expression enhanced shikonin-induced p21 promoter activity, whereas the suppression of Egr1 expression by small interfering RNA attenuated the ability of shikonin to induce p21 promoter activity. Conclusion Our results suggested that the anti-proliferative activity of shikonin was due to its ability to induce cell cycle arrest via Egr1-p21 signaling pathway. Thus, the work stated here validates the traditional use of shikonin in the treatment of cancer.

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