Journal Article

Ginsenoside Rh2 induces cell cycle arrest and differentiation in human leukemia cells by upregulating TGF-β expression

Kyung-Sook Chung, Sung-Hee Cho, Ji-Sun Shin, Dong-Hyun Kim, Jung-Hye Choi, Sang Y. Choi, Young K. Rhee, Hee-Do Hong and Kyung-Tae Lee

in Carcinogenesis

Volume 34, issue 2, pages 331-340
Published in print February 2013 | ISSN: 0143-3334
Published online November 2012 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgs341
Ginsenoside Rh2 induces cell cycle arrest and differentiation in human leukemia cells by upregulating TGF-β expression

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The triterpene saponin ginsenoside Rh2 has been shown to have antiproliferative effects on various cancer cells. However, the effect of Rh2 on the cell cycle and its underlying molecular mechanism in human leukemia cells are not fully understood. In this study, we found that Rh2 inhibited the proliferation of human leukemia cells concentration- and time-dependently with an IC50 of ~38 µM. DNA flow cytometric analysis indicated that Rh2 blocked cell cycle progression at the G1 phase in HL-60 and U937 cells, and this was found to be accompanied by the downregulations of cyclin-dependent kinase (CDK) 4, CDK6, cyclin D1, cyclin D2, cyclin D3 and cyclin E at the protein level. However, CDK inhibitors (CDKIs), such as p21CIP1/WAF1 and p27KIP1, were gradually upregulated after Rh2 treatment at the protein and messenger RNA (mRNA) levels. In addition, Rh2 markedly enhanced the bindings of p21CIP1/WAF1 and p27KIP1 to CDK2, CDK4 and CDK6, and these bindings reduced CDK2, CDK4 and CDK6 activities. Furthermore, Rh2 induced the differentiation of HL-60 cells as demonstrated by biochemical assays and the expression levels of cell surface antigens. In addition, treatment of HL-60 cells with Rh2 significantly increased transforming growth factor-β (TGF-β) production, and cotreatment with TGF-β neutralizing antibody prevented the Rh2-induced downregulations of CDK4 and CDK6, upregulations of p21CIP1/WAF1 and p27KIP1 levels and the induction of differentiation. These results demonstrate that the Rh2-mediated G1 arrest and the differentiation are closely linked to the regulation of TGF-β production in human leukemia cells.

Journal Article.  6401 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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