TRAIL Enhances Shikonin Induced Apoptosis through ROS/JNK Signaling in Cholangiocarcinoma Cells

Abstract

Background/Aims: Cholangiocarcinoma (CCA), arising from varying locations within the biliary tree, is the second most common primary liver malignancy worldwide. Shikonin, an active compound extracted from the Chinese herb Zicao, holds anti-bacterial, anti-inflammatory, and anti-tumor activities. However, the effect of shikonin on human cholangiocarcinoma and detailed mechanisms of TRAIL enhancement remains to be elucidated. The purpose of the study was to investigate the protective functions of TRAIL enhancement for shikonin induced apoptosis in cholangiocarcinoma cells. Methods: We use MTT assay, apoptosis assay, caspase activity assay, flow cytometry assay, real time PCR and Western blot to observe the effects of TRAIL on shikonin induced cholangiocarcinoma cells apoptosis and its mechanism. Results: Shikonin inhibited cell viability and induced apoptosis of CCA cells, effects enhanced by TRAIL treatment via activation of caspase-3, -8, -9. Furhermore, TRAIL enhanced anti-proliferation of shikonin and shikonin induced apoptosis through induction of ROS mediated JNK activation, while AKT activation had an effect on shikonin anti-proliferation activity, but not in the TRAIL enhanced counterparts. Finally, shikonin upregulated DR5 expression, an effect essential for TRAIL-enhanced activities of shikonin in RBE cells. Conclusions: Our results revealed that shikonin could inhibit cells viability and induce apoptosis of CCA cells, effects enhanced by TRAIL treatment via ROS mediated JNK signalling pathways, involving up-regulation of DR5 expression. Our results provide further insight into the mechanism underlying the anti-tumor effects of shikonin by TRAIL enhanced in CCA and a new therapeutic strategy to CCA treatment.

Non‑cytotoxic doses of shikonin inhibit lipopolysaccharide‑induced TNF‑α expression via activation of the AMP‑activated protein kinase signaling pathway

“…Consistent with these studies, the present results indicated that shikonin-activated AMPK could scavenge LPS-induced ROS generation. Previous studies have also shown that shikonin can increase the intracellular ROS level via various mechanisms, leading to oxidative stress and cytotoxicity (34,58,59). However, the present results are inconsistent with these existing studies.…”

“…Zicao is believed to possess detoxification properties and has been used for the treatment of macular eruptions, measles, sore-throat, carbuncles and burns (33). Shikonin, a naphthoquinone compound, is the primary active constituent of Zicao, which can be produced from the dried root of Lithospermum erythrorhizon (34). Shikonin has been reported to exert multiple pharmacological effects, including both anti-cancer and anti-inflammatory properties (35,36).…”

The Critical Role of PTEN/PI3K/AKT Signaling Pathway in Shikonin-Induced Apoptosis and Proliferation Inhibition of Chronic Myeloid Leukemia

“…Shikonin (C 16 H 16 O 5 ) is a naturally occurring naphthoquinone compound in the root of herb Lithospermum erythrorhizon and shows pleiotropic effects on some diseases, including anti-tumor, antiischemic, anti-inflammatory, and anti-bacterial effects as well as acceleration of tissue granulation proliferation [4]. Shikonin also inhibited cells viability and induced apoptosis of Cholangiocarcinoma cells, effects enhanced by TRAIL treatment via ROS mediated JNK signalling pathways [5]. Previous reports suggested that shikonin could induce oxidative activities and apoptotic effects in HL-60 cells [6].…”

N-Acetyl-Glucosamine Sensitizes Non-Small Cell Lung Cancer Cells to TRAIL-Induced Apoptosis by Activating Death Receptor 5

“…However, studies have shown that many types of cancers, including some NSCLCs, are resistant to the apoptotic effects of TRAIL [32, 37-39]. It has been reported that absence of DR expression and clustering may be a major cause of resistance to TRAIL-based cancer therapy [18].…”