Shikonin sensitizes A549 cells to TRAIL-induced apoptosis through the JNK, STAT3 and AKT pathways

Chang Zhen Liu,Yi Wang,Yan Yan Ma,Zhen Xiao Sun,Peng Huang,Zhi Lan Guo,Lu Yang Che,Jing Zhe Li,Bing Pan,Ju Ying Zhong,Dan Qian,Meng Meng Jin

doi:10.1186/s12860-018-0179-7

Abstract

BackgroundTRAIL, tumor necrosis factor-related apoptosis-inducing ligand, can selectively kill cancer cells with little or no cytotoxicity toward normal human cells and is regarded as a potential relatively safe antitumor drug. However, some cancer cells are resistant to TRAIL-induced apoptosis. Thus, reagents that potentiate TRAIL-induced cytotoxicity are needed. Herein, we investigated whether shikonin, a natural compound from the root of Lithospermum erythrorhizon, can sensitize TRAIL-resistant cells to TRAIL-induced cytotoxicity.ResultsThe viability of A549 cells, which were resistant to TRAIL, was significantly decreased after treatment with TRAIL followed by shikonin. The underlying mechanisms by which shikonin sensitizes cells to TRAIL-induced cytotoxicity were also examined. Combined treatment with shikonin and TRAIL activated the caspase and JNK pathways, inhibited the STAT3 and AKT pathways, downregulated the expression of Mcl-1, Bcl-2, Bcl-xL, c-FLIP and XIAP and upregulated the expression of Bid.ConclusionsIn conclusion, the results indicated that shikonin sensitized resistant cancer cells to TRAIL-induced cytotoxicity via the modulation of the JNK, STAT3 and AKT pathways, the downregulation of antiapoptotic proteins and the upregulation of proapoptotic proteins.

Highlights

TRAIL, tumor necrosis factor-related apoptosis-inducing ligand, can selectively kill cancer cells with little or no cytotoxicity toward normal human cells and is regarded as a potential relatively safe antitumor drug
The present study investigated whether shikonin can sensitize TRAIL-resistant cells to TRAIL-induced cytotoxicity and whether combined treatment with shikonin and TRAIL is cytotoxic to normal cells
In cells pretreated with shikonin, TRAIL noticeably decreased the viability of A549 cells over time

Summary

Introduction

TRAIL, tumor necrosis factor-related apoptosis-inducing ligand, can selectively kill cancer cells with little or no cytotoxicity toward normal human cells and is regarded as a potential relatively safe antitumor drug. We investigated whether shikonin, a natural compound from the root of Lithospermum erythrorhizon, can sensitize TRAIL-resistant cells to TRAIL-induced cytotoxicity. Tumor necrosis factor-related apoptosis-inducing ligand, TRAIL, is a promising antitumor drug because it can induce apoptosis in cancer cells but is minimally cytotoxic to normal cells [1, 2]. Studies have shown that shikonin may be similar to TRAIL in its ability to selectively kill cancer cells while causing minimal cytotoxicity to normal cells [7, 10, 14].

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Conclusion