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Lithium enhances TRAIL-induced apoptosis in human lung carcinoma A549 cells
Yan Lan1, Xiufeng Liu, Rong Zhang
1The State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, 210093, China.
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.
Insights
Lithium chloride (LiCl) sensitizes non-small cell lung cancer (NSCLC) A549 cells to TRAIL-induced apoptosis by up-regulating death receptors and activating caspases. LiCl also causes G2/M arrest via JNK inhibition, enhancing TRAIL
Area of Science:
- Molecular Biology
- Cancer Research
- Pharmacology
Background:
- Non-small cell lung cancer (NSCLC) A549 cells exhibit resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis.
- Overcoming TRAIL resistance through sensitizing agents is a potential therapeutic strategy for NSCLC.
Purpose of the Study:
- To investigate the potential of lithium chloride (LiCl) as a sensitizing agent to overcome TRAIL resistance in NSCLC A549 cells.
- To elucidate the molecular mechanisms underlying LiCl-mediated sensitization to TRAIL-induced apoptosis.
Main Methods:
- Treatment of A549 cells with LiCl and/or TRAIL.
- Assessment of apoptosis, death receptor expression (DR4, DR5), caspase activation, cell cycle progression (G2/M arrest), and c-Jun N-terminal kinase (JNK) activity.
- Pharmacological inhibition of JNK using SP600125 and investigation of glycogen synthase kinase-3β (GSK3β) involvement.
Main Results:
- LiCl significantly enhanced TRAIL-induced apoptosis in A549 cells.
- LiCl upregulated death receptors DR4 and DR5, activated caspase cascades, and induced G2/M arrest.
- LiCl inhibited JNK activity, and JNK inhibition mimicked LiCl's effects on G2/M arrest and TRAIL-induced cell death, independent of GSK3β.
Conclusions:
- LiCl sensitizes NSCLC A549 cells to TRAIL-induced apoptosis via a caspase-dependent pathway involving death receptor signaling.
- LiCl-induced G2/M arrest, mediated by JNK inhibition, contributes to enhanced TRAIL sensitivity.
- The TRAIL sensitization effect of LiCl is independent of GSK3β inhibition.