Sesquiterpene Lactones Downregulate G2/M Cell Cycle Regulator Proteins and Affect the Invasive Potential of Human Soft Tissue Sarcoma Cells

Birgit Lohberger,Beate Rinner,Andreas Leithner,Ehsan Bonyadi Rad,Nicole Stuendl,Heike Kaltenegger,Eva Bernhart,Rudolf Bauer,Bibiane Steinecker-Frohnwieser,Nadine Kretschmer,Annelie Martina Weinberg,Kamyar Afarinkia

doi:10.1371/journal.pone.0066300

Birgit Lohberger, Beate Rinner + Show 10 more

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https://doi.org/10.1371/journal.pone.0066300

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Journal: PloS one	Publication Date: Jun 14, 2013
Citations: 52	License type: CC BY 4.0

Affiliation: Medical University of Graz, University of Graz

Abstract

Soft tissue sarcomas (STS) represent a rare group of malignant tumors that frequently exhibit chemotherapeutic resistance and increased metastatic potential. Many studies have demonstrated the great potential of plant-derived agents in the treatment of various malignant entities. The present study investigates the effects of the sesquiterpene lactones costunolide and dehydrocostus lactone on cell cycle, MMP expression, and invasive potential of three human STS cell lines of various origins. Both compounds reduced cell proliferation in a time- and dose-dependent manner. Dehydrocostus lactone significantly inhibited cell proliferation, arrested the cells at the G2/M interface and caused a decrease in the expression of the cyclin-dependent kinase CDK2 and the cyclin-dependent kinase inhibitor p27Kip1. In addition, accumulation of cells at the G2/M phase transition interface resulted in a significant decrease in cdc2 (CDK1) together with cyclin B1. Costunolide had no effect on the cell cycle. Based on the fact that STS tend to form daughter cell nests and metastasize, the expression levels of matrix metalloproteinases (MMPs), which play a crucial role in extracellular matrix degradation and metastasis, were investigated by Luminex® technology and real-time RT-PCR. In the presence of costunolide, MMP-2 and -9 levels were significantly increased in SW-982 and TE-671 cells. Dehydrocostus lactone treatment significantly reduced MMP-2 and -9 expression in TE-671 cells, but increased MMP-9 level in SW-982 cells. In addition, the invasion potential was significantly reduced after treatment with both sesquiterpene lactones as investigated by the HTS FluoroBlock™ insert system.

Highlights

Saussurea lappa Clarke (Asteraceae) is a plant traditionally used in different Asian medicine systems
The chemical structures from costunolide and dehydrocostus lactone isolated from Saussurea lappa were represented in Figure 1A and 1B
We examined the effect of these compounds on the expression of cell cycle checkpoint proteins in Soft tissue sarcomas (STS) cell lines

Summary

Introduction

Saussurea lappa Clarke (Asteraceae) is a plant traditionally used in different Asian medicine systems. It has been reported that sesquiterpene lactones induced G2 arrest in human cancer cells, which may be correlated with the induction of apoptosis [5,6,7,8]. Our previous study has shown that dehydrocostus lactone inhibited cell proliferation and caused an enhanced caspase 3/7 activity, cleaved caspase-3, and cleaved PARP, indicating apoptosis induction in human sarcoma cell lines, and led to a G2/M phase arrest [9]. The molecular responsibility for the therapeutic activity and the cellular mechanisms underlying the action of sesquiterpene lactones in the induction of cell cycle arrest in sarcoma cells remains unknown. Cell proliferation is a tightly controlled process consisting of multiple checkpoints responsible for the regulation of abnormal cell cycle progression. Transitions between G1, S, and G2/M phases are regulated by biochemically coordinated actions of cyclins, cyclin-dependent kinases (CDKs), CDK inhibitors, all of which can in turn be modulated by diverse intracellular signals transduced from extracellular growth cues [10]

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