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Cancer Chemotherapy and Pharmacology

, Volume 82, Issue 5, pp 829–838 | Cite as

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

  • Min Huang
  • Hong Zhu
  • Cheng Yi
  • Juan Yan
  • Lijia Wei
  • Xi Yang
  • Shouchun Chen
  • Ying Huang
Original Article
  • 85 Downloads

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.

Keywords

TRAIL DR4/DR5 TRAIL mutant membrane-penetrating peptide-alike (TMPPA) Apoptosis Pancreatic cancer 

Notes

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).

Compliance with ethical standards

Conflict of interest

The authors have no conflict of interest to declare.

Ethical approval

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

Supplementary material

280_2018_3658_MOESM1_ESM.tif (16 mb)
Supplementary material 1 (TIF 16365 KB)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Pathophysiology, West China School of Basic Medical Sciences and Forensic MedicineSichuan UniversityChengduPeople’s Republic of China
  2. 2.Department of PhysiologyChengdu Medical CollegeChengduPeople’s Republic of China
  3. 3.Department of Medical Oncology, West China HospitalSichuan UniversityChengduPeople’s Republic of China
  4. 4.Chengdu Huachuang Biotechnology Co., Ltd.ChengduPeople’s Republic of China

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