Ginkgolic Acid C 17:1, Derived from Ginkgo biloba Leaves, Suppresses Constitutive and Inducible STAT3 Activation through Induction of PTEN and SHP-1 Tyrosine Phosphatase.

Abstract

Ginkgolic acid C 17:1 (GAC 17:1) extracted from Ginkgo biloba leaves, has been previously reported to exhibit diverse antitumor effect(s) through modulation of several molecular targets in tumor cells, however the detailed mechanism(s) of its actions still remains to be elucidated. Signal transducer and activator of transcription 3 (STAT3) is an oncogenic transcription factor that regulates various critical functions involved in progression of diverse hematological malignancies, including multiple myeloma, therefore attenuating STAT3 activation may have a potential in cancer therapy. We determined the anti-tumor mechanism of GAC 17:1 with respect to its effect on STAT3 signaling pathway in multiple myeloma cell lines. We found that GAC 17:1 can inhibit constitutive activation of STAT3 through the abrogation of upstream JAK2, Src but not of JAK1 kinases in U266 cells and also found that GAC can suppress IL-6-induced STAT3 phosphorylation in MM.1S cells. Treatment of protein tyrosine phosphatase (PTP) inhibitor blocked suppression of STAT3 phosphorylation by GAC 17:1, thereby indicating a critical role for a PTP. We also demonstrate that GAC 17:1 can induce the substantial expression of PTEN and SHP-1 at both protein and mRNA level. Further, deletion of PTEN and SHP-1 genes by siRNA can repress the induction of PTEN and SHP-1, as well as abolished the inhibitory effect of drug on STAT3 phosphorylation. GAC 17:1 down-regulated the expression of STAT3 regulated gene products and induced apoptosis of tumor cells. Overall, GAC 17:1 was found to abrogate STAT3 signaling pathway and thus exert its anticancer effects against multiple myeloma cells.

• Authors: Seung Ho Baek, Jong Hyun Lee, Chulwon Kim, Jeong-Hyeon Ko, Seung-Hee Ryu, Seok-Geun Lee, Woong Mo Yang, Jae-Young Um, Arunachalam Chinnathambi, Sulaiman Ali Alharbi, Gautam Sethi, Kwang Seok Ahn
• Journal: Molecules (Basel, Switzerland) (Molecules) Vol. 22 Issue 2 (Feb 13 2017) ISSN: 1420-3049 [Electronic] Switzerland
• PMID: 28208828 (Publication Type: Journal Article)

Chemical References

• Interleukin-6
• Plant Extracts
• STAT3 Transcription Factor
• Salicylates
• ginkgolic acid
• Protein Tyrosine Phosphatase, Non-Receptor Type 6
• PTEN Phosphohydrolase

Topics

• Apoptosis (drug effects)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Ginkgo biloba (chemistry)
• Humans
• Interleukin-6 (metabolism)
• Membrane Potential, Mitochondrial (drug effects)
• Multiple Myeloma (genetics, metabolism)
• PTEN Phosphohydrolase (metabolism)
• Phosphorylation (drug effects)
• Plant Extracts (chemistry, pharmacology)
• Plant Leaves (chemistry)
• Protein Binding
• Protein Tyrosine Phosphatase, Non-Receptor Type 6 (metabolism)
• STAT3 Transcription Factor (agonists)
• Salicylates (chemistry, pharmacology)