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A novel TRAIL mutant-TRAIL-Mu3 enhances the antitumor effects by the increased affinity and the up-expression of DR5 in pancreatic cancer

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Abstract

Purpose

Pancreatic cancer is a malignant tumor of the digestive system with poor prognosis and high mortality, and the treatment of pancreatic cancer still remains a major challenge. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce apoptosis selectively in cancer cells while causing virtually no damage to normal cells, which is promising for cancer therapy. However, many primary tumors and cancer cell lines including various human pancreatic cancer cell lines were found to be resistant to TRAIL-induced apoptosis. Therefore, the purpose of the study was to improve antitumor effect of TRAIL on pancreatic cancer.

Methods

The 114–121 amino acid coding sequence “VRERGPQR” of wild type TRAIL protein that was selected changed into “RRRRRRRR”, and the novel membrane-penetrating peptide-alike mutant protein was named TRAIL-Mu3. The antitumor effect of TRAIL-Mu3 was analyzed both in vitro and in vivo. Western blotting, immunofluorescence and flow cytometry were used to investigate the underlying mechanisms.

Results

TRAIL-Mu3 could enhance the antitumor effects on pancreatic cancer cell lines, and the antitumor effect of TRAIL-Mu3 was stronger than gemcitabine in vivo. The immunofluorescence results suggested that TRAIL-Mu3 could remarkably enhance the affinity to pancreatic cancer cells. The Western blot results showed that treatment with TRAIL-Mu3 caused a clear cleavage of caspase-3 and caspase-8. In addition, both the Western blot and flow cytometry suggested a significantly up-expression of DR5 in TRAIL-Mu3 group.

Conclusions

Membrane-penetrating peptide-alike mutant-TRAIL-Mu3 induced pancreatic cancer cell death more efficiently than TRAIL, and this effect was supposed to be mediated by the increased affinity to cell membrane, the up-regulation of DR5 and the enhancement of activated caspase.

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Acknowledgements

We thank Chengdu Huachuang Biotechnology Co., Ltd. for expert technical assistance.

Funding

This work was supported by Grants from the National Natural Scientific Foundation of China (No. 81301962 and No. 81372444).

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Author notes

  1. Min Huang and Hong Zhu equally contributed to the manuscript.

Authors and Affiliations

  1. Department of Pathophysiology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, 610041, Sichuan, People’s Republic of China

    Min Huang & Ying Huang

  2. Department of Physiology, Chengdu Medical College, Chengdu, 610500, Sichuan, People’s Republic of China

    Min Huang

  3. Department of Medical Oncology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People’s Republic of China

    Hong Zhu, Cheng Yi & Xi Yang

  4. Chengdu Huachuang Biotechnology Co., Ltd., Chengdu, Sichuan, People’s Republic of China

    Juan Yan, Lijia Wei & Shouchun Chen

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  1. Min Huang
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Correspondence to Shouchun Chen or Ying Huang.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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Huang, M., Zhu, H., Yi, C. et al. A novel TRAIL mutant-TRAIL-Mu3 enhances the antitumor effects by the increased affinity and the up-expression of DR5 in pancreatic cancer. Cancer Chemother Pharmacol 82, 829–838 (2018). https://doi.org/10.1007/s00280-018-3658-9

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