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Lithium enhances TRAIL-induced apoptosis in human lung carcinoma A549 cells

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Abstract

Non-small cell lung cancer (NSCLC) A549 cells are resistant to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Therefore, combination therapy using sensitizing agents to overcome TRAIL resistance may provide new strategies for treatment of NSCLC. Here, we investigated whether lithium chloride (LiCl), a drug for mental illness, could sensitize A549 cells to TRAIL-induced apoptosis. We observed that LiCl significantly enhanced A549 cells apoptosis through up-regulation of death receptors DR4 and DR5 and activation of caspase cascades. In addition, G2/M arrest induced by LiCl also contributed to TRAIL-induced apoptosis. Concomitantly, LiCl strongly inhibited the activity of c-Jun N-terminal kinases (JNKs), and the inhibition of JNKs by SP600125 also induced G2/M arrest and augmented cell death caused by TRAIL or TRAIL plus LiCl. However, glycogen synthase kinase-3β (GSK3β) inhibition was not involved in TRAIL sensitization induced by LiCl. Collectively, these findings indicated that LiCl sensitized A549 cells to TRAIL-induced apoptosis through caspases-dependent apoptotic pathway via death receptors signaling and G2/M arrest induced by inhibition of JNK activation, but independent of GSK3β.

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Acknowledgments

The authors are grateful to grants from National Key Basic Research Program from Ministry of Science and Technology (2012CB967004), the Jiangsu Provincial Nature Science Foundation (BK2011228, BZ2011048, BZ2010074, BZ2012050), the Chinese National Nature Sciences Foundation (81121062, 50973046, 31071196, 31070706).

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  1. The State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, 210093, China

    Yan Lan, Xiufeng Liu, Rong Zhang, Kai Wang, Yao Wang & Zi-Chun Hua

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  1. Yan Lan
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  2. Xiufeng Liu
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  3. Rong Zhang
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  4. Kai Wang
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Correspondence to Zi-Chun Hua.

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Lan, Y., Liu, X., Zhang, R. et al. Lithium enhances TRAIL-induced apoptosis in human lung carcinoma A549 cells. Biometals 26, 241–254 (2013). https://doi.org/10.1007/s10534-012-9607-x

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