Novel Molecular Regulators of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL)-Induced Apoptosis in NSCLC Cells.

BACKGROUND

Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively induce apoptosis in some non-small cell lung cancer (NSCLC) cells, some NSCLC cells exhibit TRAIL-resistance. The underlying mechanisms that regulate TRAIL sensitivity in NSCLC cells are not well understood. The objective of this study was to investigate molecular regulators of the TRAIL pathway in NSCLC cells.

METHODS

The TRAIL-sensitive NSCLC cell line NCI-H358 and a TRAIL-resistant cell line A549 were treated with rmhTRAIL for 24 hours. Then cell viability were measured by MTT assay, meanwhile cell cycle and apoptosis were measured by flow cytometry. Furthermore, mass spectrometry (LC-MS/MS) was used to identify the difference in the protein expression profiles. Finally, real-time PCR was performed to detect the mRNA expression of TRAIL receptors and apoptotic related proteins.

RESULTS

These results confirmed that NCI-H358 cells were sensitive to TRAIL, whereas A549 cells were resistant. Both mRNA and protein levels of voltage-dependent anion-selective channel proteinl (VDAC1), caspase9 (CASP9), and cytochrome c1 (CYC1) were upregulated in H358 cells but downregulated in A549 cells, whereas antiapoptotic protein BAG-2 was downregulated. In addition, TRAIL also causes DR5 low expression in A549 cells.

CONCLUSIONS

These results indicate that rmhTRAIL had different anti-tumor activity in different NSCLC cell lines. Downregulation of VDAC1, CYC1, CASP9, and upregulation of BAG-2 might be associated with underlying TRAIL-resistance mechanisms. These findings motivated further studies to explore new therapeutic strategy overcoming TRAIL-resistance of NSCLC cells through modulating dysregulation of the proteins above.