Abstract
Compared with traditional cytotoxic cancer therapy, therapy-induced cancer cell senescence attracts much interest because it is similarly effective, has fewer side effects, and is more efficiently cleared by immune cells. In this study, we demonstrate that unlike caffeic acid phenethyl ester, caffeic acid 3,4-dihydroxy-phenethyl ester (CADPE), which is isolated from the medicinal plants Sarcandra glabra and Teucrium pilosum, inhibits human cancer cell growth and colony formation by inducing cancer cell senescence, not apoptosis. CADPE induces cell senescence and morphology changes by increasing cellular size and cytoplasmic granularity, enhancing senescence-associated β-galactosidase activity and differentiated embryo-chondrocyte expressed gene 1 expression, and blocking cell-cycle arrest in the G1 phase. To help understand the underlying mechanisms, we show that CADPE significantly suppressed the expression of Twist1 and led to the up-regulation of rat sarcoma, p53, p21WAF1/CIP1, and p16INK4a proteins in a dose-dependent manner, resulting in the hypophosphorylation of retinoblastoma protein. Furthermore, overexpression of Twist1 prevented CADPE-induced cell senescence in tumor cells. Therefore, our studies provide evidence for a novel role of CADPE in cancer cell senescence by targeting the Twist1-dependent senescence signaling pathway.
Footnotes
This work was supported by the Science and Technology Commission of Shanghai Municipality [Pujiang Program Grant 09PJ1403900]; the National Natural Science Foundation of China [Grants 30800653, 81071437, 30800627]; and the Fundamental Research Funds for the Central Universities and 973 Program [Grant 2010 CB529704].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.111.181081.
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The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- SA-β-gal
- senescence-associated β-galactosidase
- CAPE
- caffeic acid phenethyl ester
- CADPE
- caffeic acid 3,4-dihydroxyphenethyl ester
- DEC1
- differentiated embryo-chondrocyte expressed gene 1
- Ras
- rat sarcoma
- pRB
- retinoblastoma tumor suppressor
- SRB
- sulforhodamine B
- TCA
- trichloroacetic acid
- PI
- propidium iodide
- PARP
- poly(ADP)-ribose polymerase
- PCR
- polymerase chain reaction
- EGFP
- enhanced green fluorescence protein
- DMEM
- Dulbecco's modified Eagle's medium
- HUVEC
- human umbilical vascular endothelial cell
- NF-κB
- nuclear factor κB
- FACS
- fluorescence-activated cell sorting
- WT
- wild type
- STAT3
- signal transducer and activator of transcription 3 .
- Received March 2, 2011.
- Accepted July 11, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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