Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising antitumor agent. However, many melanoma cells show weak responses to TRAIL. Here, we investigated whether Icariside II (IS), an active component of Herba Epimedii, could potentiate antitumor effects of TRAIL in melanoma cells. Melanoma cells were treated with IS and/or TRAIL and cell death, apoptosis and signal transduction were analyzed. We showed that IS promoted TRAIL-induced cell death and apoptosis in A375 melanoma cells. Mechanistically, IS reduced the expression levels of cFLIP in a phospho-STAT3 (pSTAT3)-dependent manner. Ectopic expression of STAT3 abolished IS-induced cFLIP down-regulation and the associated potentiation of TRAIL-mediated cell death. Moreover, IS-induced reactive oxygen species (ROS) production preceded down-regulation of pSTAT3/cFLIP via activating AKT, and the consequent sensitization of cells to TRAIL. We also found that IS treatment down-regulated cFLIP via ROS-mediated NF-κB pathway. In addition, IS converted TRAIL-resistant melanoma MeWo and SK-MEL-28 cells into TRAIL-sensitive cells. Taken together, our results indicated that IS potentiated TRAIL-induced apoptosis through ROS-mediated down-regulation of STAT3/cFLIP signaling.
Highlights
Malignant melanoma is a highly aggressive and treatment-resistant cancer, with increasing incidence and high mortality rates worldwide
We found that IS potentiated Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis assayed by annexin V/PI staining (Figure 1C)
We examined whether exotic expression of cellular FLICE-like www.impactjournals.com/oncotarget inhibitory protein (cFLIP) could abrogate the sensitization of IS on TRAILinduced cytotoxicity and apoptosis
Summary
Malignant melanoma is a highly aggressive and treatment-resistant cancer, with increasing incidence and high mortality rates worldwide. The 5-year survival rate of advanced melanoma was less than 10% [1]. Primary melanoma without any evidence of metastases is mostly treated by surgery. Chemotherapeutic agents such as dacarbazine and temozolomide (alkylating agents), targeted drugs such as vemurafenib and dabrafenib (targeting the BRAFV600E mutation) for melanoma are currently used in the clinic, CTLA-4 and PD-1 antibodies represent an effective treatment option for metastatic melanoma and other cancer entities [2, 3]; they are not suitable for many patients because of toxicity, lack of the BRAFV600E mutation, and/or developmentof resistance.
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