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Claudin-7 suppresses the cytotoxicity of TRAIL-expressing mesenchymal stem cells in H460 human non-small cell lung cancer cells

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Abstract

Evidence suggests that the cytokine tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising candidate for cancer therapeutics. Studies have also shown that claudin-7 (CLDN7) expression is variably dysregulated in various malignant neoplasms, with a role in lung cancer that has not been definitively decided. This work investigated the differential sensitivity of CLDN7-overexpressing human NSCLC H460 cells to TRAIL in vitro and in mouse xenografts, and explored the molecular mechanisms responsible for these effects. NCI-H460 cells were transfected or not with green fluorescent protein-tagged CLDN7. Each group was then exposed to mesenchymal stem cells (MSCs) or red fluorescent protein-tagged MSCs transduced with lentivirus expressing membrane-bound TRAIL. The effects and related mechanisms of these treatments were evaluated in vitro, and in vivo in murine xenografts. Our results indicate that TRAIL induced apoptosis in H460 cells in vitro, and in established xenograft tumors TRAIL was associated with a decrease in tumor size, tumor weight, and circulating tumor cells. CLDN7 was found to inhibit the MEK/ERK signaling pathway, leading to inhibition of death receptor 5 (TNFRSF10B). The cytotoxicity of TRAIL was confirmed in H460 cells and in vivo, and CLDN7 suppressed the cytotoxicity of TRAIL in H460 cells. Our results indicate that TRAIL may be a useful therapy to enhance apoptosis in CLDN7-negative lung cancer cells.

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Acknowledgments

We thank Dr Jin-Jin Wang for providing mesenchymal stem cells.

Conflict of interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, School of Basic Medical Science, China Medical University, Shenyang, 110001, People’s Republic of China

    Pu Xia

  2. Department of Pathophysiology, School of Basic Medical Science, China Medical University, Shenyang, People’s Republic of China

    Wei Wang

  3. Department of Clinical Pharmacology, College of Pharmacy, China Medical University, Shenyang, People’s Republic of China

    Yang Bai

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  1. Pu Xia
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  2. Wei Wang
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Correspondence to Pu Xia.

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Pu Xia and Wei Wang contributed equally to the work.

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Xia, P., Wang, W. & Bai, Y. Claudin-7 suppresses the cytotoxicity of TRAIL-expressing mesenchymal stem cells in H460 human non-small cell lung cancer cells. Apoptosis 19, 491–505 (2014). https://doi.org/10.1007/s10495-013-0938-z

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