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CAPE promotes TRAIL-induced apoptosis through the upregulation of TRAIL receptors via activation of p38 and suppression of JNK in SK-Hep1 hepatocellular carcinoma cells

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Caffeic acid phenethyl ester (CAPE), a phenolic compound derived from honeybee propolis, has been reported to possess anticancer activities in several types of malignant cells. Here, we show that treatment with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in combination with CAPE significantly sensitized SK-Hep1 cells to TRAIL-induced apoptosis. The sensitization to TRAIL was accompanied by the activation of extrinsic and intrinsic apoptotic pathways, leading to the activation of caspases, mitochondrial disruption and PARP cleavage. Moreover, TRAIL receptors, such as DR4 and DR5 were significantly upregulated by CAPE treatment, and both DR4/Fc and DR5/Fc chimera markedly abrogated apoptosis induced by CAPE and TRAIL, demonstrating the critical role of these death receptors in combination-induced apoptosis. The effect of CAPE on mitogen-activated protein kinases (MAPKs) was further examined, where CAPE treatment resulted in the activation of p38 and the inhibition of JNK, without affecting levels of phospho-ERK. Our results showed that p38 and JNK exhibited the opposite role in SK-Hep1 cells. The inhibition of p38, using SB203580, blocked the CAPE-induced expression of death receptors and attenuated the combinationinduced apoptosis, suggesting the pro-apoptotic role of p38. In contrast, JNK-specific inhibition, by SP600125, triggered upregulation of DR4 and DR5, and sensitized SK-Hep1 cells to TRAIL, indicating that the CAPE-induced suppression of JNK may contribute to the sensitizing effect of CAPE through the upregulation of death receptors. Taken together, these results indicate that CAPE potentiated TRAIL-induced apoptosis in SK-Hep1 cells, through upregulation of TRAIL receptors via modulation of p38 and JNK signaling pathways.
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Document Type: Research Article

Affiliations: College of Pharmacy, Sookmyung Women's University, Seoul 140-742, Republic of Korea

Publication date: January 1, 2013

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  • The International Journal of Oncology provides an international forum for the publication of the latest, cutting-edge research in the broad area of oncology and cancer treatment. The journal accepts original high quality works and reviews on all aspects of oncology research including carcinogenesis, metastasis, epidemiology, chemotherapy and viral oncology. Through fair and efficient peer review, the journal is dedicated to publishing top tier research in the field, offering authors rapid publication as well as high standards of copy-editing and production. The International Journal of Oncology is published on a monthly basis in both print and early online.
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