Comparing to traditional cytotoxic cancer therapy, therapy-induced cancer cell senescence treatment attracts much interest due to its similar effective, less side effect, and more efficiently cleared by immune cells. In this study, we demonstrate that unlike CAPE (caffeic acid phenethyl ester), CADPE (caffeic acid 3,4-dihydroxy-phenethyl ester), which is isolated from 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-gal activity and DEC1 expression, and blocking cell-cycle arrest in G1 phase. To understand the underlying mechanisms, we show that CADPE significantly suppressed the expression of Twist1, and leads to the up-regulation of Ras, p53, p21WAF1/CIP1, and p16INK4a proteins in a dose-dependent manner, and as a result, the hypophosphorylation of pRB. Furthermore, overexpression of Twist1 prevented CADPE-induced senescence in tumor cells. Therefore, our studies provide evidence for a novel role of CADPE in cancer cell senescence by targeting Twist1-dependent senescence signaling pathway.
- Received March 2, 2011.
- Revision received July 11, 2011.
- Accepted July 11, 2011.
- The American Society for Pharmacology and Experimental Therapeutics